Pathophysiology fall term 1 2020 Module 1
What is Pathophysiology?
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 Pathophysiology is the study of the functional changes that happen to our cells, tissues and
organs as a result of disease or injury.
 Knowledge of normal human anatomy (structure) and physiology (function) is integral to the
understanding of these pathophysiological changes.
Why study Pathophysiology?
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 Understanding pathophysiology helps the nurse to recognize the underlying mechanisms of
disease that the patient is manifesting as clinical signs and symptoms.
 Nurses use pathophysiology every time they come in contact with a patient!
Pathology vs. Pathophysiology
Pathology
Pathophysiology
•Study of structural (anatomical/physical)
changes in cells, tissues and organs caused by
•Study of physiological (functional) changes in
disease or injury
molecules/biochemistry, cells, tissues and organs caused
•Biopsy or autopsy findings are used to make a by disease or injury
diagnosis of disease and prognosis of healing
•Pathologist uses findings/diagnostics to determine diagnosis, prognosis and treatment
protocol
Biopsy tissue removal from living individual
Autopsy (post mortem)
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tissue removal following death of individual
tissue samples from either source will undergo microscopic, genetic, biological and/or
chemical diagnostic analysis
Findings
• the diagnostics; results of the laboratory and imaging tests utilized by the pathologist to
determine diagnosis, prognosis and treatment protocol
Diagnosis
• the identification of the specific disease
Therapy/therapeutics
• the method of treatment of the disease/illness with the goal of curing or at least reducing the
patient’s signs and symptoms to a level of (near) normal function
Prognosis
• the expected outcome of the disease
Pathogen
• Pathogen
• The disease-causing organism/causative agent
• Sometimes called antigen (self or foreign chemical that elicits immune response)
• Pathogenicity
• The ability of a pathogen to cause disease
Pathogenic success depends on:
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Communicability
Virulence
Extent of tissue damage
Host susceptibility
3 most susceptible groups for sickness
Very young (missing antibody) – between 1 to 2
very old (immune system is slow)
and auto immune compromised people
Antigens:
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chemicals (usually proteins) that elicits an innate and/or adaptive immune response
may be self-antigens or foreign antigens
Disease vs. Illness
DISEASE ILLNESS
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o
o
o
Homeostatic imbalance occurs Individual feels ‘unhealthy’
Diagnostic Proof Medical History
Clinical Manifestations (Signs & Symptoms)
Able to adapt and Difficulty with activities continue with
activities of daily living of daily living
Disease
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Is the abnormal condition; the homeostatic imbalance
Causes variations of cellular structure and/or function that are considered outside of the
normal range and result in a loss of the homeostatic balance required for optimal
cellular functioning
Illness
• Suggests that the individual is aware of the homeostatic imbalance
The presence of a homeostatic imbalance causing pathophysiologic manifestations can be
detected using diagnostic tools e.g. blood glucose, presence of intracellular enzymes in
extracellular fluids such as blood plasma
ADL = activities of daily living
Etiology
The cause of the disease and/or injury
3 broad etiologic categories:
1. Genetic Etiology
2. Congenital Etiology
3. Acquired Etiology
When explaining the cause of a disease, one of these 3 categories should be used in the
description. You will see that within each category there may be many subcategories.
Genetic Etiology
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 Cause is a genetic abnormality
 What is a genetic abnormality?
o  Chromosomal defect/mutation, or
o  Genetic defect/mutation
o  Leads to underproduction or overproduction of a particular ___chromosome_______
therefore affecting normal biochemistry/cell functioning
 Inherited traits; familial (genetic) predisposition ‘runs in the family’
 Family Hx?
o  Developmental effects
o  Increased susceptibility to specific disease(s)
 Manifestations may be present at or shortly after birth or develop years later
What are genes? What is their function?
Genes are specific regions of DNA; each gene codes for and regulates synthesis of a specific
protein
Chromosomal defect/mutation
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Includes additions or deletions or translocations of entire sections of chromosomes e.g.
5p minus syndrome, deletion of the short arm of chromosome 5 (aka Cri du Chat)
Includes additions or deletions of entire chromosomes
e.g. Trisomy 21 or Turners syndrome 45X or XO)
Genetic defect/mutation
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Implies that a single gene or a group of genes on a single chromosome is/are defective
A genetic mutation (e.g. a single gene deletion or addition or even the addition, deletion
or switching of a single nitrogenous base (A, T C or G) may cause the gene coding for a
particular protein to be defective→a defective gene does not allow for proper protein
synthesis; lack of a particular protein or production of the wrong protein can result in a
biochemical change that may be detrimental to the individual
e.g. cystic fibrosis, hemophilia, sickle cell disease and phenylketonuria (PKU) are all
genetic disorders that affect production of normal body proteins
Genetic and chromosomal disorders often have developmental effects
e.g. Down’s syndrome (Trisomy 21) often manifests with mental and physical issues such as
increased risk of learning disorders, cardiac abnormalities and earlier onset of dementia
Inheritable traits may cause increased disease susceptibility
e.g. UV skin damage in those with very fair or very dark complexions
e.g. increased risk of early onset heart disease in families with hypercholesterolemia or sickle
cell disease
Chromosomal and genetic disorders
1. Down syndrome: chromosomal defect, extra
chromosome in autosomal pair 22; results in
trisomy 21
2. Sickle cell anemia: genetic defect (point
mutation), faulty gene expression incorrectly
replaces one amino acid in the protein
hemoglobin; the hemoglobin sickles in a lower
than normal oxygen environment lots of
microthrombi develop and block blood flow
Congenital Etiology
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 Result of a genetic defect or due to some injury/exposure that occurred during
embryonic or fetal development in utero or during labour and delivery of the child
 Sometimes called a birth defect since disorder may be present at birth
 Includes: mental deficits, physical anomalies, malformations and some diseases or
syndromes
 If due to intrauterine exposure to a teratogen, timing of exposure is significant to degree of
malformation
 1st trimester exposure/embryonic period has most severe outcomes
 Major organs affected: Brain, heart, eyes, ears, limbs and palate – why?
 Common manifestations include:
• Mental deficiency, motor control deficiency, structural heart defect, blindness, deafness
and/or cleft palate
Remember TORCH
Toxoplasmosis, other, rubella, cytomegalovirus, herpes simplex(virus 2)
In utero means within the uterus (i.e. intrauterine).
Can you define the embryonic vs fetal periods of human development?
✓Embryonic development: beginning of week __2______ to end of week _____8___
• Most dangerous period for intrauterine exposure to teratogens
✓Fetal development: beginning of week ________ to end of week ________
• Developmental issues may still occur but usually not as severe as with embryonic exposure
✓What are some problems that can occur during labour and delivery of the child?
Teratogen:
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A substance or condition that impairs normal embryonic or fetal development, causing
fetal deformity
Timing of exposure greatly influences susceptibility and resulting degree of
malformation
First trimester of pregnancy, especially the embryonic period, is when organogenesis
(development of organs) and limb development are rapid – CNS, eyes, ears and heart
are all developing rapidly during this time - a time when many women do not even know
they are pregnant
Exposure to teratogens from conception to implantation (first 1 – 2 weeks) is unlikely to
cause birth defects since this pre-embryonic period does not rely on maternal blood
supply for support
Red zone: Organs most sensitive to embryonic (beginning of week 3 to end of week 8 of
gestation) teratogen exposure
Notice that fetal brain development is sensitive to teratogens throughout entire pregnancy –
there is no safe time period for exposure to teratogens such as alcohol or nicotine or heroin or
cocaine
Common teratogens
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To remember the common teratogens, use the
TORCH acronym
The TORCH acronym was originally created for
teratogenic infectious agents
O – ‘other’ category has been expanded to include
other infectious agents + other known chemical
teratogenic agents and radiation exposure
Other infections: coxsackie virus, hepatitis, HIV,
parvovirus, syphilis, V-Z virus, Zika virus, Lyme
disease
Other chemicals: maternal smoking - causes low
birth weight (LBW) due to decreased placental
perfusion (nicotine causes arteriole vasoconstriction, including placental arterioles,
resulting in less nutrient and oxygen rich blood reaching developing embryo or fetus),
exposure to alcohol - associated with a variety of potential physical, neurological and
behavioral changes that are collectively categorized as fetal alcohol spectrum disorder
(FASD). The umbrella of FASD includes diagnosis of fetal alcohol effects (FAE) and the
more severe fetal alcohol syndrome (FAS).
Radiation is both teratogenic and mutagenic (i.e. causes gene mutations that are
harmful)
1. Thalidomide exposure caused upper limb defects in 1950s and early 1960s.
2. Cleft palate has been linked to a variety of factors, including maternal cigarette
smoking.
✓Which classes of pharmaceuticals should not be used in pregnant women?
________________________
Acquired Etiology ❖Most common etiology category
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Genetics and intrauterine embryonic/fetal development are normal; damage occurs after birth or
later in life
Includes environmental factors
General causes of acquired tissue damage:
 Infectious agents (microbial, biological)
 Physical agents
 Chemical agents
 Malnutrition – includes nutritional, fluid & electrolyte and pH imbalances
 Abnormal immune responses
 Psychological agents
Environmental factors include: air pollutants; air or water borne organisms; ergonomic factors
Physiological pH is the normal pH of blood and body cells
❖Normal physiological pH range is 7.35 – 7.45 with an average of 7.4
Interstitial fluid = the fluid found between the body cells within a tissue, aka tissue fluid or
intercellular fluid
Details of causes of respiratory or metabolic acidosis or alkalosis are discussed in other
courses. For our purposes – respiratory means cause is due to a respiratory issue and metabolic
means the cause is due to some other body system issue that involves biochemical change.
Ascites fluid – increase in the fluid volume and pressure within the peritoneal cavity; often
indicated liver damage
Match the term related to possible disease etiology with the correct example
_c__ Idiopathic a. “ I went to the hospital to have my baby and now I have a really bad gut infection”
__a_ Iatrogenic b. Nurse did not properly wash hands prior to changing a surgical dressing
__b_ Nosocomial c. “I’m sorry but we don’t know the cause of the seizure”
Idiopathic - the cause of the disease is unknown
Iatrogenic - the cause of the disease and/or injury is related to a medical intervention e.g.
surgery, drug side effects
Nosocomial - disease is acquired as a result of being in a hospital environment; aka health careassociated diseases e.g. hospital borne infection such as Clostridium difficile
Risk Factors “Triggers”
Predisposing Risk Factors
 Increase the possibility of developing a disease or injury; NOT the actual cause of the
disease
Precipitating Risk Factors
 Actually causes the disease or injury to develop
 Two Types of Risk Factors
1. Modifiable risk factors
 Lifestyle, environment
2. Non-modifiable risk factors
 Age, genetics (inherited), gender
A predisposing risk factor increases the chance of developing a specific issue
e.g. family history of heart disease
A precipitating risk factor will actually lead to the development of a specific issue
e.g. sedentary lifestyle in combination with smoking lead to heart disease
Both predisposing and precipitating risk factors may be further categorized as modifiable or
non-modifiable risk factors.
Modifiable risk factors can be changed by the individual e.g. lifestyle or environment
Non-modifiable risk factors cannot be changed e.g. your age, genetics, gender
Clinical example: Predisposing (Risk) Factors for Atherosclerosis
➢Below is a randomized list of modifiable and non-modifiable risk factors for
atherosclerosis (the build up of fatty plaque in arteries) that leads to a multitude of possible
health issues. Choose which risk factors are modifiable and which are non-modifiable.
Male gender (XY)
Smoker
Periodontal disease
Hypertension
Family history of early onset heart disease
↑ plasma LDL/cholesterol > 65 years of age Overweight
Sedentary lifestyle
Diabetes mellitus (Type 1 or 2)
Modifiable risk factors can be changed by the individual e.g. lifestyle or environment
Non-modifiable risk factors cannot be changed e.g. your age, genetics, gender
LDL – low density lipoprotein and cholesterol – part of blood lipid profile, high levels are linked
to increased risk of fatty plaque in arteries
It is the hyperglycemia associated with diabetes mellitus that increases the risk of
atherosclerosis.
Risk Factors for Atherosclerosis
Non-modifiable Risk Factors
Male gender
Modifiable Risk Factors
↑ plasma LDL/cholesterol
↑ plasma LDL/cholesterol
Smoker
*Overweight
Sedentary lifestyle
> 65 years of age
Family history of early onset heart disease
Type 1 or Type 2 DM
Type 1 or Type 2 DM*
Periodontal disease
*Hypertension
*Hypertension
*Family history of early onset heart disease
*Cause disease sequelae that can lead to further, chronic health issues
Note: notice the number of rows on each side! These answers are randomized in importance
within each heading
Sequelae
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Unwanted outcomes of a disease or trauma that can lead to further, often chronic
health issues
Example: smoking or periodontal disease or weight gain or DM→increases risk of
atherosclerosis→atherosclerosis increases risk of hypertension→hypertension increases
risk of cardiovascular disease→HTN, MI, stroke, kidney disease →dialysis and peripheral
neuropathy→limb gangrene→limb amputation
Pathogenesis
Pathogenesis
• The pathologic, physiologic or biochemical pattern of tissue changes leading to development of
disease
• Sequence (chain) of events leading to the structural/functional changes associated with the disease
or injury
• Explains how the disease evolves/progresses over time
• From first contact with etiological agent until disease or injury becomes evident (i.e. clinical
manifestations present)
Disease pathogenesis asks the question “how does this disease progress over time?”
Remember:
Pathologic = structural changes
Pathophysiologic = functional changes/effects
Biochemical = body’s chemical and metabolic changes/effects – fluids, electrolytes, nutrients,
wastes
• Changes in structural, functional and/or biochemical mechanisms leads to homeostatic
imbalance with resultant clinical manifestations
Pathogenesis
• Explains the pattern of tissue changes associated with the development of disease
•This flow chart illustrates the principal elements involved
in disease pathogenesis.
Pathogenesis
•Normally begins when a causative (etiological) agent causes some form of initial damage that
affects normal cellular function that can subsequently produce broader effects in tissues,
organs and organ systems
•Notice that each stage of disease pathogenesis may produce characteristic signs and
symptoms (i.e. clinical manifestations).
Parenchyma vs Stroma
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 Within an organ, there are two groups of cells – those responsible for the specific function of
that organ and those that support the functional cells
 Parenchymal cells – the functional cells of the organ
 Did they survive the injury? Can they reproduce?
 Stromal cells – the supportive framework of connective tissue, blood vessels and
lymphatic vessels and nerve endings (receptors)
1) Brain
2) Heart
Answer the questions regarding these 2 histology slides:
1) In this brain slide, the neurons are the _______parenchyma ______________
(parenchymal/stromal) cells and the neuroglial cells are the ____stroma_____________
(parenchymal/stromal) cells.
2) The heart wall is made of 3 layers.
Label each layer as either parenchyma or stroma:
________stroma ______________ epicardium (made of serous membrane)
_________parenchyma _____________ myocardium (made of cardiac muscle cells)
__________stroma ____________ endocardium (made of endothelium)
All organs are made of a combination of parenchymal and stromal cells. In wound healing, you
will learn about the different abilities of cells to survive injury - this is called regenerative
potential. For injured tissues to return to normal pre-injury function, both parenchymal and
stromal cells are required. If scarring occurs, it is made by stromal fibroblasts.
Morphological Change
 Morphology
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 The shape/size of cells
 Specific to each cell type; required for the cell to function normally
 Morphological change
 Adaptive property of damaged cells as they try to survive the injury
 Pathologists
 Study changes in cellular morphology to diagnose disease
 Researchers
 Study effects of new Tx and new etiological agents at the cellular level
Type 1 DM morphologic changes A and B are normal
Morphology is the science of structure and form; in this case the structure and form of cells
and tissues. You may recall the histology section of A and P. Each subtype of epithelial,
connective, muscle or nervous tissue had cells with unique structures and functions.
Morphological changes that occur to cells as they adapt to injury is discussed in detail in the
altered cells and tissues section of this course. If cells cannot adapt, they die.
Pathologists utilize morphologic change in the diagnosis of disease.
Researchers utilize morphologic change to study the effects of new Tx and new etiological
agents at the cellular level. If a pharmaceutical company wants to market a new drug, changes
to parenchymal or stromal morphology are part of the potential side effects that must be
proven to not be overly severe.
The specifics of types of adaptive cellular changes will be discussed in the altered cells section
of this course.
Types of Acquired Etiologies
Infectious agents
(aka microbial/biological) - may have direct or
indirect (via toxin production) effects on the host
(i.e. infected individual)
Physical agents – external causes of homeostatic
imbalance
Examples
Bacteria, viruses, fungi, chlamydia, rickettsiae,
mycoplasma, parasites (protozoa, helminths),
insect vectors (bites and stings), prions (infectious
proteins) and food poisoning
Mechanical trauma e.g. compression, MVA;
temperature (thermal) trauma (i.e. heat and cold);
Radiation (UV light, repetitive x-rays, radon gas);
noise pollution; electric shock
Chemical agents - exposure to abnormally high or
Poisons, Toxins, Heavy metals – neurologic
low level of a specific chemical (inhaled, ingested or damage, possible carcinogens, Hypoxia (low tissue
transdermal) exposure
O2)
Nutritional Imbalances
*Name the 6 classes of nutrients!
Carbohydrates (CHO), Lipids (fats), Proteins,
Vitamins, Minerals, Water.
Fluid and Electrolyte Imbalances
o Fluid = water + dissolved solutes (e.g. Na+, K+,
Cl-)
o Edema – excess tissue (interstitial) fluid (i.e.
swelling)
o Third spacing – occurs when fluid shifts out of
the bloodstream and in to a body cavity or
interstitial space and is no longer part of the
circulating blood plasma or lymph e.g. ascites
Abnormal Immune Responses
Malnutrition – poor nutritional status
o Overnutrition – excessive consumption of 1 or
more class of nutrients; may cause toxicities;
obesity
o Undernutrition – insufficient ingestion or
production of 1 or more class of nutrients; may
cause specific deficiencies or more systemic effects
(starvation, anorexia)
o Overhydration – excess fluid intake or
insufficient fluid losshypervolemia
o Underhydration – insufficient fluid intake or
excessive fluid losshypovolemia, dehydration
o Acidosis – decrease in physiological pH (< 7.35) o
Respiratory acidosis e.g. asthma
o Metabolic acidosis e.g. diabetic acidosis
o Alkalosis – increase in physiological pH (>7.45) o
Respiratory alkalosis e.g. hyperventilation o
Metabolic alkalosis e.g. alkaline drug OD
o Hypersensitivities ‘allergies’ – immune system
overreacts to relatively innocuous (not harmful)
environmental agents/antigens
o Local effects e.g. asthma or hives
o Systemic effects e.g. anaphylaxis
o Autoimmunity – immune system reacts to
normal
self (auto) antigens e.g. Type 1 diabetes mellitus o
Immunodeficiencies – immune system does not
elicit a normal response to foreign antigen e.g. AIDS
Psychological agents
General Adaptation Syndrome (GAS)
Role of stress in disease – ‘fight or flight’ response,
chronic stress, PTSD
Lesion
 The actual site(s) of tissue damage; the ‘wound’
Classification of Lesions:
 Local lesion
 Limited to specific body part or region
 Focal lesion- in one spot of the body -doesn’t spread
 Diffuse lesion – in one part of the organ but spreads through the organ (uti)
 Systemic lesion
 Widespread damage (fever)
Although local lesions are limited to one body organ or body region, they are often further
subclassified into focal or diffuse lesions.
Focal lesion
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The tissue damage is within a specific site within an organ or body part
e.g. palmar surface of the left hand
Diffuse lesion
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The tissue damage is within one organ or body part but the damage is uniformly
distributed throughout that organ or body part
e.g. the entire liver is affected in the fatty liver histopathology slide above
Systemic lesion
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Tissue damage is widespread across several body systems
e.g. metastatic cancer
• The bone scan illustrated in this slide is an example of widespread systemic lesion e.g.
prostate cancer with many metastatic (secondary) sites including bone metastases.
Clinical Manifestations
 Includes the signs and symptoms (S & S) of
disease/injury
Signs
Symptoms
•Detectable, testable patient information
•Objective e.g. vital signs
•Patient’s experiences
•Obtained by health care professional during
physical examination, laboratory test or medical
procedure
Examples: blood glucose, x-ray, biopsy, redness,
swelling, fever
•Subjective
•Part of patient medical Hx
Examples: pain level, malaise, anxiety, headache,
fatigue
Hx = history
Examples of measurable signs include: TPR, BP and heart or lung sounds on auscultation, blood
tests, imaging or biopsy results. Signs may be local or systemic. Note: NCLEX prefers to use the
term clinical manifestations to the term’s signs and symptoms. Be sure to know all these
definitions.
This slide depicts the medical interventions that may occur during a disease/ tissue injury state.
You will notice that nurses may be involved at several steps!
•The medical/patient history, physical examination and clinical manifestations are all part of the
health assessment - mechanism used to determine the specific plan of care for an individual
patient.
•Based upon the patient’s response to therapy, knowledge of the disease
pathogenesis and clinical experience of the medical professional
-osis = abnormal condition of
Disease Onset (Clinical Course)
Disease Onset
•The time over which the disease or condition develops
•Classifications: acute, chronic, insidious, latent/dormant, subclinical/subacute
Example of diseases
Classification of disease on set
Hypertension
Chronic
Bullying at school
subclinical
Broken leg
Acute
Myocardial infraction
Acute
Cystic fibrosis
Chronic
HIV infection
Latent dormant
This slide includes examples of several disease conditions. Use this list of terms to classify the
timing of disease onset of each example: acute, chronic, insidious, latent/dormant,
subclinical/subacute. We will complete this chart in class.
Disease onset
• the time of first appearance of signs and symptoms of disease
Classification of disease onset is as follows:
Acute condition
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Rapid or sudden onset of signs and symptoms
Short duration (time frame is somewhat arbitrary, possibly hours – days)
Self-limiting
e.g. food poisoning
Chronic condition
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Rapid or slow (insidious) onset
Continuous, longer duration (possibly weeks – months); possibly lifelong
Latent/dormant condition
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Asymptomatic period of quiescence before signs and symptoms manifest
E.g. HIV, shingles
Subclinical (subacute) condition
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Intermediate between acute and chronic
Symptoms not as severe as acute and do not last as long as chronic disease
Signs may not be detectable; i.e. not producing effects that are detectable by clinical
tests
Note: the terms disease onset and clinical course are interchangeable.
Disease Course
Disease Course
 How does the disease ‘behave’ over time?
 Acute vs chronic disease course
 If acute?
 Disease course measured in days to ~ 2 weeks
 Examples?
 If chronic?
 Disease course measured in weeks, months...
 Disease progression may include remissions and
exacerbations
Clinical disease course of multiple sclerosis (MS)
 Examples?
Disease course is used to describe the continuous progression; how the disease clinical
manifestations and tissue morphological changes develop, proceed and/or change over time. A
patient history which includes a time frame is an important component in describing the course
of a specific disease.
What is the difference between an acute and a chronic disease course?
Acute disease course
• Time frame from illness to wellness measured in days to about 2 weeks (allows time for
adaptive immune response to an antigen, if necessary)
Chronic disease course
•Time frame from illness to wellness measured in weeks, months or longer
•If the disease is described as chronic in nature then the terms remission or exacerbation may
be used to describe the disease progression
Remissions
•periods where clinical manifestations disappear completely or are significantly decreased
Exacerbations
•periods where clinical manifestations become more obvious and severe **often called “flare
ups”
In this figure of the disease course of MS notice that the patient exhibits further physical
deficits after each exacerbation of the disease. MS is an autoimmune disease that will be
discussed in detail in Pathophysiology 2.
Note: refer back to the definition of disease onset and compare these two terms. Disease onset
= time frame of disease development - did you suddenly become ill? Disease course = time
frame of disease progression – did your illness change over time?
Clinical Infectious Disease Course
 Etiology? Acquired; microbial source of disease
 Transmissible: Contagious! Infectious! Communicable!
 4 distinct stages of infectious disease course:
 Initial exposure to microbe, followed by
1. Incubation period - asymptomatic
2. Prodromal stage – non-specific manifestations e.g.
tired, cranky (most contagious stage)
3. Invasion period – specific disease manifestations;
e.g. sore throat (you can see it)
4. Convalescence – recovery time
➢When is the infected person contagious and able to transmit the disease? Imidiate after exposure
➢When are they most contagious? Prodromal
➢Who is most susceptible? Young, old, immune compromised
➢Significance of vaccination programs? Get vaccinated
These are terms associated with microbial infections, so refer to any microbiology text for
further information.
Following initial exposure to the microbe, there are 4 distinct stages of infectious disease
course:
1) Incubation period
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Time from initial exposure to the infectious agent to the onset of the first symptoms
Microorganisms have colonized, invaded and are multiplying but infected individual is
still asymptomatic although they may be contagious.
2) Prodromal stage
• Initial non-specific symptoms of infection occur – usually mild such as tiredness, discomfort.
*Most contagious stage, but individual often doesn’t realize it.
3) Invasion period
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Microbial infection is multiplying quickly and spreading to other tissues/organs either
locally or systemically, depending on severity.
Clinical manifestations specific to the disease-causing organism are present as
inflammatory and immune responses are triggered to fight the infection – pain, malaise,
headache, generalized aching, loss of appetite and other G-I effects, skin rashes, etc.
Note: if fever develops, that is a sign of a systemic infection.
4) Convalescence
• Time required to return to health and strength after illness.
Note: infectious = contagious = communicable = transmissible
Name the stage of the disease course of this infection
Mumps – infect salivary gland – and testes and ovaries
Public Health Agency of Canada (PHAC) is very interested in communicable diseases! Why?
•Communicable diseases are infectious and easily transmitted from one individual to others
and causes disease in most exposed individuals
•Common communicable diseases include: measles, mumps, pertussis (whooping cough),
chicken pox, cold and flu (influenza), diphtheria, amoebic dysentery
•Notice that vaccines are available to prevent many of these diseases
•Usually air borne or water borne
•Who is most susceptible to communicable diseases? Young old immune deficient
•Explain the significance of vaccines in the control of communicable disease transmission
Why are ‘boosters’ required for these vaccines?
Portal of Entry (Mode of Transmission)
 How did the pathogen enter the body?
 4 Modes of Entry:
1.
2.
3.
4.
Transdermal (direct contact)
Inhalation
Ingestion
Injection
➢Body systems most commonly compromised?
Physical barriers – skin and mucus membranes
In this case, the pathogen is not necessarily microbial.
e.g. pollutants, heavy metals, radiation
Injection – includes needles and bites/stings from animals or insects
Your skin and mucous membranes are major components of your innate (born with it) defense
against foreign invaders. When they are compromised, cell injury will occur.
Transplacental transmission could cause a congenital defect.
Syndrome
Disease or condition has a defined group of lesions and signs and symptoms with a common etiology eg.
Down syndrome
1 genetic – 2 acquired 3 – congenital – 4 aquired /congenital
• The term syndrome may be part of a disease’s name e.g. Down syndrome, AIDS, Fetal Alcohol
Syndrome or Reye syndrome
Different syndromes have different etiologies. Some syndromes have multifactorial etiologies
There are many different syndromes. Can you think of some others?
Down syndrome – trisomy 21
AIDS – HIV infection
FAS – alcohol exposure in utero
Reye syndrome – result of aspirin use in children with specific viral infections (e.g. flu or chicken
pox)
Complication
Disease or condition that occurs in addition to the original tissue damage – examples?
Classic illnesses: telltale signs
Measles complications Mnemonic: MEASLESCOMP
Myocarditis Encephalitis (brain damage )
Appendicitis
Subacute sclerosing panencephalitis (brain damage)
Laryngitis (baby laryngitis = croup)
Early death
Shit (diarrhea)
Corneal ulcer
Otis media
Mesenteric lymphadenitis (lymph nodes in the gut)
Pneumonia and related (bronchiolitis-bronchitis- croup)
Complications can change the prognosis of a disease.
e.g. measles infection→encephalitis→permanent brain damage
This measles complications mnemonic is for illustrative purposes only. You do not need to
memorize it!
Note: how many of these childhood diseases can be prevented by vaccination?
Epidemiology
 Study of the distribution and determinants of health in a specific population and application of this
information to control the specific health problem
 Asks: Who is at risk? Where is the risk? When did the health issue begin? How is it spread? How is it
controlled?
 Agencies involved:
 World Health Organization (WHO)
 National Microbiology Lab (NML) Winnipeg
 Center for Disease Control (CDC) atlanta gorgia
 Public Health Agency of Canada (PHAC)
Where is the National Microbiology Laboratory (NML) located? Where is the Center for Disease
Control (CDC) located?
WHO definition of health (1948 constitution)
‘a state of complete physical, mental and social well-being and not merely the absence of
disease or infirmity’
Epidemiology (cont’d)
Prevalence
Number of existing cases in a population/specific time
Common? Rare?
Incidence
Number of new cases in a population/specific time Contained? Spreading?
Terminology associated with epidemiology
Prevalence – asks the question: How common is the disease right now?
Incidence – asks the question: How fast is the disease spreading right now?
2020 has been a very busy year for epidemiologists. These are the people trying to keep track
of the prevalence and incidence of the global pandemic, Covid-19.
Endemic
Disease has high, but constant rates of infection within a particular population
 Examples? Tb manitoba
Epidemic
Number of new infections within a particular population far exceeds expected occurrence
 Examples? Tb up north
Pandemic
Epidemic that is spread over large area of population – continental, global
Historic examples? Current examples? Covid 19
More epidemiology terminology – which definition(s) suggest that incidence is increasing?
Endemic – always present within population/location
E.g. TB in Canada’s northern communities
E.g. Malaria in parts of Africa
Epidemic – health agencies are always watching for these changes in infection rates E.g. TB and
HIV in Canada’s northern communities
Eg. Influenza outbreaks
E.g. Ebola in West Africa
E.g. Zika in South America
Pandemic – health agencies on high alert
E.g. Covid-19 is not mentioned in the video but is a very significant disorder that all of us are
being affected by right now.
Notifiable (Reportable) Disease
 Required by law to be reported to public health authorities. Why?
 Listed by Public Health Association of Canada (PHAC)
 http://dsol-smed.phac-aspc.gc.ca/dsol-smed/ndis/list-eng.php
Mortality Rate



 Death rate due to specific disease/cause in a specific population or time frame
 Often stated as a % within a population
 Impacts public health policy
Morbidity Rate
 Incidence/rate of a specific disease/cause in a specific population
 Possible long-term health consequences for the individual
 Impacts health care costs
A notifiable disease must be reported by medical personnel immediately upon diagnosis in an
attempt to prevent further spread (i.e. epidemic occurrence).
Take a look at the PHAC list but do not memorize it. You will discuss many of these diseases in
Microbiology.
Mortality rates and their effect on public health policy and the law? Here are a few examples:
• seat belt use, texting while driving, pre-school vaccination, cigarette packaging... can you think
of some others?
Morbidity rates also affect public health policy because they impact our health care costs.
Here are a few examples:
• work related repetitive strain injury→osteoarthritis chronic pain→loss of work + increased
use of health care
• obesity→increased risk of Type 2 diabetes→hypertension→cardiac event→increased use
of health care
... can you think of some others?
What are co-morbidities? the simultaneous presence of two chronic diseases or
conditions in a patient
Epigenetics
 The study of chemical modifications of DNA, histones or RNA that alter the expression of genes
(the phenotype), resulting in cellular differentiation or disease
Gene expression: mechanisms that turn genes ‘on’ or ‘off’
 These chemical modifications occur ‘above’ or ‘on top’ of our standard understanding of genes; thus the
name epigenetics
 E.g. oncogenes, some hypersensitivities, stress-related diseases, in utero influences (malnutrition, alcohol
exposure, BPA exposure)
Epigenetics is a new topic in pathophysiology and will be discussed later in this course. Much
current research into disease mechanisms and future treatments revolves around epigenetics.
Remember, genes are small sections of your chromosomal DNA. Each gene controls the
production of a specific protein. These proteins then help in the normal function of the cell that
produces the protein or are secreted from the cell to aid in normal homeostatic mechanisms
elsewhere in the body. A change in gene expression can change the amount of a particular
protein produced and thus can change body homeostasis.
Here are a few examples to help you relate to this term:
•Exposure to cigarette smoke→proto-oncogenes ‘turned on’→oncogenes change gene
expression→increased production of proteins that stimulate cell growth→neoplasm
•Chronic stress→increased epinephrine and cortisol secretion→change in endothelial cell gene
expression→decreased endothelial cell protective proteins→increased endothelial cell
damage→atherosclerosis→hypertension→cardiovascular disease
•Endothelial cells are the cells that line all blood vessels, heart valves and lymphatic vessels
•BPA – bis-phenol-A and phthalates – plastics-derived endocrine disruptors that affects pubertal
and adult reproductive development
1. Congenital diseases are familial diseases. T/F
2. The current outbreak of measles in Europe is a pandemic. T/F
3. Sleep deprivation is a sign of stress. T/F
4. Vaccines can prevent acquired infections. T/F
5. Mucous membranes are common infection portals of entry. T/F
6. Communicable diseases are often airborne. T/F
7. High morbidity rates mean many people have died. T/F
8. Convalescence is the last stage of a clinical infectious disease course. T/F
9. Morphological change indicates cancer. T/F
10. Disease indicates the individual is unable to perform activities of daily living. T/F
Foundations of Pathophysiology Worksheet Answer Key
1. 1. True or false:
a. It is better to be highly susceptible to a pathogen than to have low susceptibility. F
b. The more virulent the pathogen, the easier it is to treat the patient. T or F
c. Communicable infections spread quickly through dense populations. T or F
d. Air and water borne infections are highly contagious. T or F
JT visits Urgent Care. He has a severe headache and cannot touch his chin to his chest. His temperature
is 39.7 C, pulse is 110 bpm and respirations are 26/min. Blood work shows elevated neutrophils and
lymphocytes.
1. What are JT’s signs? Testable, objective, determined by medical personnel – i.e temperature, pulse,
respirations, and differential WBC - elevated neutrophils and basophils, nuchal rigidity (chin to chest difficulty
indicates irritation of meninges
2. What are JT’s symptoms? Patient’s perspective, subjective – severe headache
3. What are the findings? Findings – the diagnostics – diff WBC –% of each type of WBC within the total WBC
population; elevated WBCs indicate acute (neutrophils) viral (lymphocytes) infection
4. What is a possible diagnosis? Meningitis – probably viral infection
5. What is a possible prognosis? Will depend on virulence of viral infection and patient’s susceptibility and
response to treatment – hopefully good with medical intervention
3. CASE STUDY #2
Ebola outbreak in West Africa 2016 update
1. What is the etiology of Ebola? Etiology – the cause: Viral infection – acquired - infective ZOOL 1073 © AM
Kowatsch
Foundations of Pathophysiology Worksheet Answer Key 2
2.
3.
4.
5.
What is the epidemiologic origin of this outbreak? Western Africa
What is the mode of transmission of Ebola? Contact with infected blood and bodily fluids
What is the incubation period? 2 – 21 days post-exposure
Ebola has many clinical manifestations.
a. State the signs. Temperature (if taken), presence of rash and red eyes; bloody diarrhea, bloody vomit
and
bleeding through the nose, mouth and eyes
b. State the symptoms flu-like illness – high fever, general aches and pain, lethargy, headache and
stomach upset
c. Which clinical manifestations are local? Rash, red eyes, G-I mucous membrane bleeding d. Which
clinical manifestations are systemic? Fever and elevated WBCs (leukocytosis)
6. What is the incidence of this Ebola outbreak? Several ( >3-<10)/week
7. What is the prevalence of this Ebola outbreak? 28, 000/ total West African population (367 million;
UN
2015 statistics; not given in the question)
8. What is/are the risk (predisposing) factors? Contact with blood or bodily fluids during care of the ill family
member or during the traditional bathing and preparation of the deceased by family members
9. Is Ebola an acute or chronic illness? acute
10. What is the prognosis? Without medical treatment – poor <20%, with treatment - ~50% -patients die of
hypovolemic shock due to hemorrhage and severe dehydration
11. What is the mortality rate without medical intervention? 80%
12. Ebola virus is highly communicable. True or False? Explain your answer. False – airborne or water borne
infectious agents are much more communicable; Ebola requires direct contact with blood or bodily fluids.
13. At what stage of the disease course is Ebola most contagious? Prodromal stage when manifestations are
still non-specific
14. What is the main treatment for Ebola? Rehydration and blood donation
15. Briefly describe the pathogenesis of Ebola. Pathogenesis – how the disease progresses over time An
infected individual exhibits flu-like illness – high fever, general aches and pain, rash, red eyes, lethargy, head ache
and stomach upset. As the virus replicates and destroys mucous membranes, the illness may progress to bloody
diarrhea, bloody vomit and bleeding through the nose, mouth and eyes – the hallmarks of hemorrhagic fever. The
virus is shed through all of these bodily fluids. Death usually occurs within 1 week of onset of serious illness.
Module 1 ends ---
Module 2 begins
Mechanisms of Defense and Repair
- Inflammation and Wound Healing
1st Canadian Ed. Chapter 6 (inflammation and wound healing) and Chapter 23 (p. 589- 593;
review of blood vessel A and P)
Mechanisms of Defense and Repair
✱ Types of WBCs and their basic functions ✖
Part 1: The Inflammatory Response
✖Part 2: Wound Healing
Discussed during
lectures
Comparison of
Innate and
Adaptive Defenses
in the Body
iNNATE DEFENSES
Fluids
Non-specific
Flushing: Tears,
Saliva, Mucous,
Sweat, Gastric
acid, Urine
B – cell: Antibody
mediated
responses
Barriers
T – cell: Direct
cytotoxic attack
No immunological
memory
Skin, mucous
membranes &
microbiome
Immune
Responses
ADAPTIVE DEFENSES
Specific
Long-term
immunological
memory
Phagocytosis
Ingestion by WBC
Both –
Immunological
memory response
Chemical
mediators
Histamine, acute
phase plasma
proteins, cytokines
Inflammation
Redness, heat,
swelling, pain, loss
of function
Fever
All Defenses
Overcome Injury or
Disease
First Line of Defense
Possible Outcomes
1. Mechanical(Physical)Barriers
•Epidermis of skin
•Mucous membranes •Mucous (coughing,
sneezing) ‘sticky’
•Cilia
•Hairs
•Lacrimal Apparatus (Tears)
•Saliva, Urine
•Defecation and Vomiting
Body Defenses
Successful Health or
Healing
Charachteristics
prevent entry of the foreign agent into the
body or try to expel agent
intact epidermis is your best barrier to
infection. Keratin helps prevent drying
Not as effective as epidermis; includes
flushing, (i.e. copious volume of secretion)
often works with cilia to trap foreign agent and
sweep it away from deeper structures
‘mucociliary elevator’
G-I, respiratory, urinary, reproductive tracts
transport the foreign agents trapped by
mucous Upper respiratory tract, reproductive
tracts
Trap foreign agent, filter dust Nose and ears
Flushing
flushing, acidic pH is natural bactericide
Flushing
2. Chemical Barriers associated with skin
and mucous membranes
Sebum/Cerumen
•Lysozyme
•Gastric Juice
•Vaginal Secretions
•Normal microbiome (flora)
Chemicals are toxic to pathogens or aid in the
repair process (called cytotoxic, cytolytic or
proteolytic). Acidic pH of some chemicals
inhibits bacterial growth (bacteriocidal)
Oily, acidic pH
Antimicrobial enzyme found in saliva, tears,
perspiration, nasal secretions and tissue fluids
Acidic pH
Acidic pH, mucous
Help prevent infections by more virulent
organisms G-I and vaginal tracts e.g.
Lactobacillus, Acidophilus
Second line of defense ------- characteristics
1. Antimicrobial
Discourage microbial growth
Proteins
Short acting chemicals involved in WBC communication
Includes: interleukins, colony stimulating factors (CSFs) and interferons
• Cytokines
(antivirals that protect uninfected host cells from viral infection and
prevent viral multiplication)
Complex cascade of plasma proteins that once activated, aid in
destruction of microbes by promoting : lysis of microbial cell membranes
• Complement
via membrane attack complex (MAC), phagocytosis by WBCs,
System
opsonization (to make ‘tasty’) of antigen and inflammation. Also assist in
adaptive immunity.
Express pattern recognition receptors (PRRs) such as toll-like receptors
2. Cellular
(TLRs) that can bind with broad range of molecular patterns exhibited by
Defenses
microbes
Directly attack microbes and tumor cells; apoptosis; secrete cytotoxins
• Natural Killer
(NK) Cells
(perforins, granzymes); induce apoptosis
Neutrophils (first responders), monocytes →macrophages (large
numbers), dendritic cells (skin and mucosal surfaces)
• Phagocytic
Cells
Note: macrophages and dendritic cells are the functional antigen
(Phagocytes)
presenting cells (APCs) that act as intermediaries between the innate and
adaptive immune responses
Major chemical mediator is histamine secreted by mast cells
3. Inflammatory Includes vasodilation, increased vascular permeability, and phagocyte
response
migration
5 cardinal signs of inflammation
Hypothalamus determines normal set point of body T
4. Fever (pyrexia)
↑ temp due to effect of circulating pyrogens on hypothalamus
3rd third line of defence
Adaptive immunity
o First exposure to antigen ? slower to manifest than innate responses takes about 7-14 days
o Response improves with each re exposure to specific antigen – faster and more specific
o Specific immunological memory occurs – faster response with re exposure
o Third line of defense – 2 lymphocytes types with different mechanisms of deploying
o Humoral (antibody mediated immunity)
o B lymphocytes deffirientiate into plasma cells – production of antigen specific
antibody / immuniglobulin which binds to and results in destruction of antigen
(igA, igD,igF,igG,igM classes.
o Cell mediated immunity
o T lymphocytes production of antigen specific higher t cells stimulate other t cells
and b cells and cytotonic t cells bind to and stimulate apoptotic destruction of
antigen cell
Some WBCs are innate immune cells, others function in
adaptive immunity.

Innate immune cells include: basophils,
dendritic cells, eosinophils, Langerhans cells, mast cells,
monocytes and macrophages, neutrophils and NK cells.

Adaptive immune cells include: B cells and T cells.
B cells, which are derived from the bone marrow,
become the cells that produce antibodies.
✓If you don’t remember what these terms mean or which cells are involved in innate vs
adaptive immune function, do a quick review using your text and the resources posted on
Learn.
Meet your Immune Cell Team!
✖ Promote inflammation:

+ Basophils Secrete HISTAMINE and other + *Mast cells
proinflammatory mediators
✖ Act as phagocytes:




+
+
+
+
*Neutrophils (PMNs) – 1st
*Macrophages (monocyte
*Dendritic cells
B lymphocytes
✖ Initiate antibody mediated


+ NK cells
+ Eosinophils
✖ also secrete histaminase (stops
responders
derived)
immunity
APC
histamine effects at end of
inflammatory event)
✖ Induce cell apoptosis:



+ NK cells
+ Eosinophils
+ Cytotoxic T lymphocytes
✖ Aided by APCs and Helper T lymphocytes
✖ Boost innate and adaptive responses: + *Helper T cells – boost everybody!
Summary of Cell – Derived Mediators
Cell derived mediator
Histamine
Cell sources
Mast cells in tissues
Basophils in blood
Physiological effects
H1 receptors –
proinflammatory;
endothelial cell contraction;
vascular smooth muscle
relaxation (vasodilation);
bronchiolar smooth muscle
contraction; neutrophil
chemotaxis
Prostaglandins (PGs)
Leukotrienes (LTs)
Damaged cell membranes of
mast cells and platelets
Platelet activating factor
(PAF)
Cytokines
Lymphocytes, macrophages,
damaged cells
•Interleukins (ILs)
•Interferon (IFN)
•Tumor necrosis factor α
(TNFα)
•Transforming growth factor
β (TGFβ)
Eosinophils
•Histaminase
H2 receptors – antiinflammatory; decreases
gastric juice secretion and
decreases WBC responses
All proinflammatory; weak
histamine-like effects
PGs – irritate nerve endings
and induce pain; some
subtypes stimulate smooth
muscle spasm
(vasoconstriction)
All – stimulate platelet plug
formation; promote
thrombosis
Proinflammatory: ILs, IFN
and TNFα
- Act as local communication
signals and growth factors for
WBC production; WBC
adhesion molecules, promote
WBC emigration,
chemotactic agents
- ILs – signal adaptive B and T
cell immune responses
- IFNs – viral infection alert
signals
- TNFα - produced in
response to microbial
infection, induce fever Antiinflammatory: TGFβ, IL-10
- Help regulate inflammatory
response to
•Others: chemokines (PG,
LT), lysosomal enzymes, ROS,
Substance P and nitric oxide
(NO)
Neutrophils and various
damaged cells
limit inflammatory response
- Enzymatic digestion of
histamine
proinflammatory: PGs, LTs
- Help stimulate
phagocytosis, chemotactic
agents, promote apoptosis
- Induce pain (Substance P)
- Promote vasodilation (nitric
oxide)
*Surveillance cells of the Mononuclear Phagocyte System – includes innate WBCs that are
located at common sites of entry of pathogens, such as epidermal/dermal and mucosal
surfaces; e.g. dendritic cells within epidermis/dermis and mucous membranes, various fixed
macrophages (that reside in specific tissues) and wandering macrophages that tour the
lymphatic system, blood stream, interstitium (tissue fluid) and fascial planes - constantly
looking for trouble in the form of foreign antigens; excellent phagocytes. Macrophages are
monocytes that have left the blood stream and reside and function in a specific tissue or organ;
many have organ specific names e.g. Kupffer cells in the liver, microglia in the brain, dust cells
in the lungs). These cells were discovered at different times by different scientists and named
without knowing their specific functions.
How do WBCs recognize tissue damage? Innate immune cells have receptors that recognize
and react to specific microbial membrane protein patterns or microbial by-products or even
chemicals released by your own damaged body cells – more about this shortly.
Apoptosis – programmed cell death; part of normal cell physiology - due to lack of use (e.g.
extra uterine smooth muscle cells after the baby is born) or, in the case of the inflammatory
response, targeted cell death due to the release of cytolytic chemicals by various WBCs
APCs = antigen presenting cells – phagocytize, process and present antigen fragments (pieces of
antigen attached to a cell membrane protein called MHC) to cytotoxic T cells of the adaptive
immune system. If the cytotoxic T cell has a receptor that can bind to the antigen (TCR = T cell
receptor), it will bind then attack the APC, thus destroying the antigen – this process is called
cellular mediated immunity.
Development of immune function
We are born with some innate WBCs such as intravascular neutrophils and tissue mast cells but
very few adaptive immune cells. Thus adaptive immune function is minimal at birth, becoming
fully functional by 2 years of age (even by 1 year of age most children have a fairly robust
immune response to infection; think about the importance of a child’s one year booster shots!)
PMN = polymorphonuclear leukocytes; i.e. neutrophils
2 Minute Review: Effect of
Inadequate Immune Defense
1. What happens if:
+ 1st line of defense is intact? _________no tissue damage occurs
2. What happens if:



+ 1st line of defense is breached? _______tissue damage occurs
__________________
+ 2nd line of defense is activated? _______ causes inflammation
__________________
3. Is the innate response to tissue damage fast or slow?
4. What is the purpose of an acute inflammatory response? ___removal____ of
the causative agent/pathogen →promote wound healing __
5. When does the adaptive immune system become involved?
___innate response unsuccessful ___
+ How long does it take to be fully functional? ______7-14 days -peak day 10__
6. What happens if the innate and/adaptive immune defenses are not
successful? Chronic inflammation may ensure
7. What happens if there is too much histamine released? ____Flushing is common.
Peptic ulcers may develop because too much histamine is produced, stimulating
secretion of excess stomach acid. Ulcers can cause stomach pain. Nausea, vomiting,
and chronic diarrhea may also occur
Part 1: Inflammation and the Inflammatory Response
Inflammation – the tissue response to injury or infection; 5 signs that are
considered the hallmarks of the inflammatory response
5 signs five signs of inflammatory response Heat , redness, swelling pain,
loss of function
Inflammatory response – describes how various tissues react to injury or infection that causes
tissue damage
We will discuss the 5 signs of inflammation and their development during an inflammatory
response.
Can you see all 5 cardinal signs of the inflammatory response in this slide? Do you know their
Latin terms? You may recognize some of them!
Histamine secretion – innate 2nd line of defense
igA, secretory antibody – Bcells – adaptive
tears , vomiting , diarrhea , sneezing– innate first line of defense
phagosytocis – second line of defense innate redness swelling – 2nd line of defense
ag- specific cell mediated cytokitocys The Inflammatory Response
What is inflammation?
+ Tissue response to injury from any cause
+ Occurs in vascularized tissues
+ 5 signs present
Redness, Heat, swelling , pain, loss of function
What is the inflammatory response?


+ Part of second line of innate immune defenses
+ Non-specific, rapid response of injured tissue to any
causative (etiological) agent of tissue damage
✖ What are the 3 major etiologies of tissue damage? Genetic, congenital or
acquired etiologies
+ Includes vascular, cellular and biochemical
(plasma protein) responses to tissue damage
The inflammatory response is triggered when the first line of innate defenses (i.e. skin or
mucous membranes) have been breached by the causative agent.
Recall the 3 general causes/etiologies of inflammation from the Foundations module:
1) Genetic etiology
• gene/chromosome abnormality
2) Congenital etiology
• Includes intrauterine or delivery exposure; teratogens
3) Acquired etiology (most common)
• infectious agents, physical agents, chemical agents, nutritional imbalances, fluid and
electrolyte imbalances, abnormal immune responses and psychological agents
Need a quick refresher? Review the section on the etiology of tissue damage in Foundations of
Pathophysiology.
The Inflammatory Response (cont’d)
Purposes of the Inflammatory Response
1. Limit further tissue damage
▪To destroy or dilute out causative agent
2 ) Prevent spread of injurious agent/infection
▪To wall off causative agent
3) Stimulate adaptive immune response
If inflammatory response not able to destroy causative agent
4)Begin wound healing process
a. To bring in nutrients, remove wastes (including cell debris) \
The Inflammatory Response
Role of Stromal and Parenchymal Tissues
❖Stroma (stromal tissue)
+ Microvasculature (aka microcirculation)
✖ Arterioles, capillaries, venules
✖ Endothelial cells - role in response to injury
Stromal
response to injury
triggers
inflammatory
response
Connective tissues the
✖ Especially areolar (loose) CT
✖ Fibroblasts - secrete protein fibers called collagen ✖ Mast cells – secrete
histamine
✖Parenchyma (parenchymal tissue)
+ The functional cells of the tissue
+ May be injured and need to heal or be replaced but do not directly cause the
inflammatory response; discussed with wound healing
To review microvasculature anatomy, refer to the review slides in this module on Learn or your
textbook:
Both stromal and parenchymal tissues respond to tissue damage.
Areolar CT is the most common type of CT; it will be found in every body organ that is damaged.
The two main types of cells in CT that are involved in the inflammatory response are
fibroblasts and mast cells.
Fibroblasts are stromal CT cells that secrete proteinaceous fibers that help form the framework
of all connective tissues – collagen, elastin and reticulin. Collagen is the most important
secreted fiber involved in the inflammatory response and wound healing by helping to stabilize
the wound site during wound healing. Collagen also helps trigger blood clotting (coagulation), if
necessary if blood vessels are damaged and the individual is bleeding.
Mast cells are a tissue WBC that secrete histamine during the inflammatory response.
Parenchymals are the functional cells of the organ; that means they are responsible for the
specific functions of that organ (e.g. nephrons in the kidney, neurons in the brain and spinal
cord, epithelial cells in the epidermis, muscle cells, hepatocytes in the liver, blood cells within
the cardiovascular system). They may need to heal themselves or be replaced (if possible) by
mitotic cell division. If parenchymal cells cannot be replaced tissue/organ deficits may occur.
The Inflammatory Response
2 patterns of Inflammatory Response based on:
Acute inflammatory
Chronic inflammatory response
1) the duration of response, and
+ 2) specific WBCs present in lesion
1. Acute Inflammatory Response
2. Chronic Inflammatory Response
Comparison of Acute and Chronic Inflammatory Responses
Acute Inflammation
Chronic Inflammation
 ✖ Innate, immediate tissue
 ✖ Innate and adaptive, prolonged
response to injury
tissue reaction to continued injury or
 ✖ Tries to limit the damage and
persistent infection – innate and
adaptive
prevent scarring
 ✖ Still trying to limit the damage and
 ✖ Promotes wound healing by
promote wound healing, but scarring
bringing in nutrients and
(fibrosis) probable
removing debris
 ✖ Predominant immune cells:
 ✖ Predominant immune cells:
macrophages and lymphocytes
neutrophils and macrophages
➢We will study
the two patterns of
inflammation
individually.
Recall that neutrophils and macrophages are innate immune cells and lymphocytes are both
innate and adaptive immune cells.
Within a chronically inflamed site, you will see aspects of acute (newly injured) and chronic
inflammatory responses to the persistent causative agent of injury.
A few macrophages (M1) reside within all normal, healthy connective tissues. However, once an
inflammatory response is triggered, chemicals released by microbes, damaged body cells and
dead and dying neutrophils stimulate a massive influx of new monocytes into the injury site.
These monocytes immediately undergo morphological change to become macrophages (M2).
These M2 macrophages are commonly known as the ‘clean up’ cells; these phagocytes tend to
show up a bit later in the acute inflammatory response and promote wound healing. M2
macrophages will stick around and work with the lymphocytes if the wound site becomes a
chronic issue.
Notice that all tissue injury will initiate an acute
inflammatory response. In a healthy individual, the
acute inflammatory response will have a successful
outcome. The causative agent will be destroyed or
removed and the wound will heal with minimal or no
permanent deficits. This is the best case scenario. If
the immune system is unable to successfully remove
the causative agent or if the causative agent of the
injury is not removed (e.g. genetic disorder or a
repetitive strain injury), then the tissues enter a
chronic inflammatory state.
A tissue suffering from chronic inflammation will show areas of acute inflammation and of
attempted wound healing. Newly injured or reinjured tissues will demonstrate aspects of acute
inflammation, previously injured tissues may exhibit aspects of attempted wound healing. The
term ‘repair’ implies that scar tissue has been produced. In wound healing, regeneration and
resolution are the preferred outcomes. A hallmark of chronically inflamed tissues is,
unfortunately, scarring.
We will revisit the concept of wound healing as the last topic in Module 2.
Acute Inflammatory Response
Acute Inflammatory Response
Characteristics of the Acute Inflammatory Response
✖ Begins immediately (within seconds!)
✖ Innate immune response - second line of defense
+ Non-specific; no memory cells
✖ Includes proinflammatory biochemical and cellular responses
✖ Major Chemical Mediator: histamine released by mast cells
✖ Major Cellular Mediators:
✖ Mast cells – secrete histamine
✖ Neutrophils – phagocytic; ‘first responders’
✖ Beneficial process

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+ Brings in nutrients
+ Helps dilute causative agent
+ Helps remove causative agent
+ Initiates adaptive immune responses
+ Helps prepare injured area for wound
infection &limit further tissue damage
healing to prevent spread of
Notice that the benefits of the acute inflammatory response are the same as those stated for
inflammation in general. Chronic inflammation is a complication of unsuccessful acute
inflammatory mechanisms that did not remove the cause of the initial tissue damage.
3 Major Components of the Acute Inflammatory Response
The Vascular Response
+ Immediate histamine-mediated response by wound site microvasculature
endothelial and smooth muscle cells
The Cellular Response
+ WBC, platelet and RBC responses to injured tissue’s distress signals
The Plasma Protein Systems Response
Biochemical responses to injury; transported in blood plasma Includes 3 Cascades of
Acute Reactant Proteins:
Complement system – innate immune 2nd line defense
Coagulation (clotting) system – forms blood clots
Kinin system – innate immune 2nd line defense
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Please note that 2) has expanded to include all 3 types of blood cells.
Immune cells: another term for WBCs
The inflammatory response begins with the release of histamine from granules stored
within mast cells. Release of histamine is known as mast cell degranulation.
A cascade of events is also known as a domino effect. Once the first domino falls, it
triggers the tumbling of the next and so on...
In the case of the 3 plasma protein systems, pre-formed proteins are circulating in the
blood plasma as soluble inactive proteins. Once the first protein in the cascade is
activated – by tissue injury – that protein will trigger the activation of the others within
the cascade in a specific order. If one or more of the proteins is insufficient or fails to
activate, the cascade also fails – leading to a lesser effect of that acute protein system
on the inflammatory response. Defective protein synthesis is the result of
_____deletion_________ or _______switching of a nitrogen base________ etiology
(answers in module 1)
Lack of any of the plasma protein system proteins will delay or even prevent a proper
acute inflammatory response, possibly allowing the causative agent to survive and cause
further tissue damage and/or increase potential blood loss.
Complement and kinin cascades promote inflammatory responses; they, like histamine,
are called proinflammatory mediators.
The coagulation cascade is triggered if the microvasculature is damaged; you are
bleeding and a blood clot is required. Why? If vessels are injured, clotting needs to occur
to prevent too much blood loss. Lack of a clotting protein is a cause of hemophilia; thus
hemophiliacs may suffer severe blood loss from injuries considered of a minor nature
for those with normal levels of the coagulation proteins.
✓We will discuss the 3 components of the acute inflammatory response individually.
Remember, the entire response depends on the chemical mediator called
______histamine________________ released primarily by local tissue
____mast_____________ cells!
Puss is a sign of bacteria – made of dead and
dying bacteria, body cells, white cells all are
dead or dying
Which chemicals ‘jangle’ nerve endings
causing pain (or tickle or itch). What makes
inflamed tissues red? What causes the
swelling?
3 Major Components of the Acute
Inflammatory Response (cont’d)
1. The Vascular Response
2. The Cellular Response
3. Plasma Protein Systems Response
We will now examine the specifics of each component of the acute inflammatory response
individually, beginning with the vascular response and a quick review of the
microvasculature.
Note: Black arrow indicates area where vasodilation of arteriole in response to histamine
(yellow granules) would begin. Large purple arrow in venule region indicates an error in this
figure which you need to fix if you own the 7th or 8th editions of the textbook. This label should
read emigration of agranulocytes (monocytes and lymphocytes).
Microvasculature: Effects of Histamine Stimulation
✖Microvasculature
+ the microscopic blood vessels
✖ Arterioles
✖ Capillaries (arranged in capillary beds/capillary networks)
✖ Venules – back to heart
✖ Note: Both endothelial cells (the endothelium) and vascular
smooth muscle cells contain histamine receptors→respond
to histamine
This figure should be familiar from the review slides! Be sure to
review microvasculature A and P in your text or in the review slides posted on Learn.
What are the effects of histamine release on microvasculature?
• Histamine binds to histamine receptors on both endothelial and smooth muscle cells causing:
1) arteriolar and precapillary sphincter smooth muscle cells to relax→vasodilation→more
blood enters capillary bed→redness, heat
2) venular endothelium (minor effect on capillaries) becomes more permeable→increased
vascular permeability allows intravascular fluid (i.e. plasma) to enter damaged tissue,
increasing tissue fluid volume →edema (swelling), pain, possible loss of function
Why are these microvascular responses to histamine important? 1) Local vasodilation
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occurs as arteriolar smooth muscle relaxes and precapillary sphincters open. Local
increased blood flow and increased blood hydrostatic pressure promotes passive
capillary and venule dilation within the wound site
increases blood flow to the injured site→brings in nutrients and WBCs to destroy
pathogen
2) Local increased vascular permeability
• occurs primarily in venules
• promotes the movement of nutrients, WBCs, antibodies and other proinflammatory
mediators out of the blood plasma and into the damage site AND helps to remove dead and
damaged cells and pathogens from the site (by WBC phagocytosis), necessary for wound
healing to occur
• When a tissue is injured, two smooth muscle vascular effects occur in very quick succession...
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1) Arteriolar vasospasm - immediate, but brief vasospasm as smooth muscle contracts
in response to sympathetic NS release of epinephrine (transient vasoconstrictive stress
response to injury), followed quickly by
2) Arteriolar vasodilation – smooth muscle relaxes in response to release of histamine
from degranulated local mast cells
Note: interstitium = interstitial fluid = tissue fluid
Histamine and Histamine Receptors
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Histamine is a proinflammatory vasoactive amine that effects the
microvasculature
Histamine binds to histamine receptors located on cell membrane of specific
body cells at injury site; effects vary depending on specific subtype of target cell
receptors
Two Types of Histamine Receptors:
 H1 receptors: pro-inflammatory effects
 Endothelial cells
 Vascular smooth muscle cells
 Bronchiole smooth muscle cells
 H2 receptors: anti-inflammatory effects
 Gastric parietal (HCl secreting) cells
 Immune cells
Proinflammatory – promotes inflammatory responses
Vasoactive – chemical that causes a vessel to act/respond to stimulation by that chemical
Amine – in pharmacology, this means that the chemical contains an NH2 (amine) group.
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Proinflammatory H1 mediated histamine effects trigger the 5 signs of the inflammatory
response.
Wait! What is this anti-inflammatory effect of histamine binding to H2 receptors on
stomach acid secreting gastric parietal cells and some immune cells?
 ↑ HCl secretion by gastric cells to help with protein digestion
 ↓ activity of immune cells at end of inflammation
 Why does histamine increase stomach acid secretion? What might this
mechanism help prevent?

As wound healing begins, immune cells at the site express H2 receptors which
decreases their inflammatory activity and thus helps decrease the inflammatory
response.
Effects of histamine on H1 and H2 receptors
This is a new slide that is not in the pre-recorded lecture. This information is testable.
2 Types of Histamine Receptors:
H1 receptors (proinflammatory)
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Located on vascular endothelial cells →changes gene expression →actin produced
→stimulates endothelial cell ‘contraction’→↑ vascular permeability
Located on microvascular smooth muscle cells →stimulates smooth muscle relaxation
→vasodilation
Located on bronchiole smooth muscle cells →stimulates bronchiole smooth muscle
contraction→bronchiole constriction→decreased gas exchange (e.g. asthma,
anaphylaxis)
Results? Microvascular vasodilation increases local blood flow and increased vascular
permeability sends nutrients and WBCs into wound site; bronchiole constriction may
lead to wheezing, asthma, dyspnea (discussed in Patho 2 with altered immune function)
H2 receptors (anti-inflammatory)
Located on gastric parietal cells →stimulates increased gastric acid secretion
Located on WBCs→decreases inflammatory response as wound healing begins
Pharmacology note: What are antihistamines? Drugs that are H1 histamine antagonists
– this means they block the ability of histamine to bind to H1 receptors, thus block
histamine effects on target cells that contain H1 histamine receptors.
✓Can you see why antihistamines decrease the inflammatory response?
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Endothelial and Vascular
Smooth Muscle Responses to
Histamine Stimulation
Endothelial Cells
✖ Location: venules and capillaries ✖
Physiological effect: changes
Vascular Smooth Muscle Cells
✖ Location: arterioles and precapillary
sphincters
gene expression→actin produced
✖ Physiological effect:
all cells produce actin
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+ 1) ↑ actin gene
expression→actin causes
endothelial cell ‘contraction’
→interendothelial cell gaps→↑
local vascular permeability→edema
and leukocyte infiltration
+ 2) ↓anti-adhesion molecule gene
expression→blood cells adhere to
endothelium→leukocyte infiltration
and platelet adhesion
+ 1) causes vascular smooth muscle
relaxation→arteriole vasodilation and
precapillary sphincters open →↑ local
blood flow into capillary bed (passive
vasodilation)→redness, heat and edema;
maybe pain and loss of function
This is a new slide that is not in the pre-recorded lecture. It is the same information organized
into a table for ease of studying. The content is the same as in the video.
Physiological effects of histamine are the histamine mediated responses that occur when
histamine binds to its histamine receptors (H1) on endothelial cells and vascular smooth
muscle cells. These effects will be local to the wound site.
Can these effects be systemic? Yes, during anaphylaxis (which is discussed in Patho 2).
Vascular Responses to Histamine Stimulation during Acute Inflammation include:

Arterioles – vasodilate to increase blood flow into damaged tissues as histamine relaxes
vascular smooth muscle→increased local blood flow
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Precapillary sphincters – smooth muscle relaxes to open sphincter →increase blood
flow into capillary bed →increased local blood flow
Capillaries – expand a bit in diameter as blood flow from arterioles increases pressure in
them; some increased permeability
Venules - increase vascular permeability by causing endothelial cell
contraction→interendothelial gaps allow fluid to leave plasma and enter
tissues→increased local tissue fluid
Endothelial cell contraction mechanism:
• Histamine stimulates endothelial cells to change their normal gene expression and produce a
bit of the protein actin
Actin is a normal muscle protein that is part of all muscle cell contraction
• Once produced, actin stimulates the cells retract their cell membranes a bit – think of it as the
pulling in of the edges of their outer edges which allows microscopic gaps to form between the
cells. (Often the prefix ‘myo’ is added to their name to indicate this transient process.) Plasma
components and WBCs can leak out of these gaps into the surrounding tissue fluid. Actin will
also play a role in wound healing.
Why is endothelial contraction and increased vascular permeability important to the
inflammatory response?
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Provide nutrients, destroy/dilute out/wall off causative agent
Allows infiltration of leukocytes into the wound site →phagocytosis of pathogens and
cell debris
Comparison of blood flow in normal uninjured vessel vs inflamed vessel
Transudate is the fluid the fluid that leaves the blood plasma and goes into the tissues
Histamine allows the endothelials cells to relax and dilate this inflammation
Compare the two vessels in this slide, noting the tight connections between the endothelial
cells in the first diagram of the normal capillary and the spaces between the endothelial cells in
the second figure of the inflamed capillary.
In the second diagram, actin has caused the cell membrane of the endothelial cells to pull in a
bit – to ‘contract’ its edges – which increases space between adjacent endothelial cells, forming
small intercellular (interstitial) gaps. Thus ‘myoendothelial cell’ contraction allows the vessel to
become more permeable allowing intravascular fluid (plasma) to shift from intravascular to
extravascular (tissue) compartments.
Result? Increased tissue fluid in wound site; edema.
Venule endothelial cells are particularly sensitive to histamine; thus venules are considered the
major vessels involved in the increased vascular permeability at a wound site. Myoendothelial
contraction is a very rapid response, lasting 15 – 30 min post injury.
Comparison of Blood Flow in Normal
(uninjured) Vessel vs. Inflamed Vessel
Blood flow in a Normal (Uninjured) Blood
Vessel
Blood flow in Acutely Inflamed Vessel
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Axial streaming of blood cells
Plasma in the plasmatic zone
Endothelial cells secrete antiadhesion chemicals
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‘Myo’endothelial cell contraction
→interendothelial cell gaps lead
to...
Increased venular permeability
Endothelial cells secrete proadhesion chemicals
Blood cells enter plasmatic zone
→adhere to endothelium→enter
wound site
Endothelial cells are closer to the wall
A bit of normal blood flow physiology:
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Normal blood flow is smooth, laminar flow that allows blood cells to travel in the
central (axial) zone of the blood stream (called axial streaming) and plasma to flow
against the endothelial walls of the vessel in the plasmatic zone. Since axial streaming
keeps blood cells away from the endothelial cells, blockage of blood flow in a healthy
intact blood vessel should not occur.
Plasma has a lubricating effect that prevents too much contact between the potentially
‘sticky’ blood cells and the endothelial cells lining the blood vessel wall. This lubricating
effect prevents unintentional blood cell adherence to vessel endothelial cell walls.
Healthy endothelial cells also secrete anti-adherence chemicals that help prevent all
blood cells from adhering to them.
❖Why is this important? If platelets bind to the endothelial cells, they could adhere and
trigger a coagulation (clotting) cascade. Plasma lubrication and anti-adherence chemicals help
prevent platelet adherence and possible intravascular blood clotting (thrombus formation). We
never want unnecessary intravascular thrombus formation!
❖Whereas, in the injury site:
❖Histamine stimulates changes in endothelial cell function. Actin allows endothelial cells to
change their shape creating interendothelial cell gaps, endothelial cells also stop producing
anti-adherence chemicals and may even start secreting chemicals that promote platelet and
WBC adhesion to the blood vessel wall. Blood cell-endothelial cell adhesion has its purpose. For
example, platelet adhesion to endothelial cells is important in blood clotting. WBC adhesion is
an important step in leukocyte infiltration into a wound site
❖Now, refer back to the previous slide and notice the interendothelial gaps and a WBC
adhering to the endothelium and then squeezing through the gap
acute inflammation – microvascular response
to histamine
Histamine is released from stromal mast cells into tissue fluid→diffuses into the local
capillary→binds to histamine (H1) receptors on the endothelial cells that create the lining of
the microvasculature and vascular smooth muscle cells→triggers the endothelial and smooth
muscle microvascular responses →acute inflammatory effects manifested (5 signs).
We will refer to Figure 7.4 (8th Ed.)/7.3 (7th Ed.) from your text several times in this section.
This figure is not in the 1st Canadian Edition – look for a copy of this slide in the handouts
section of this module. Please study it carefully looking for the 3 components of the
inflammatory response.
Note: Black arrow indicates area where vasodilation of arteriole in response to histamine
(yellow granules) would begin. Large purple arrow in venule region indicates an error in this
figure which you need to fix if you own the 7th or 8th editions of the textbook. This label should
read emigration of agranulocytes (monocytes and lymphocytes).
Vascular Response to histamine includes:
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Transient local arteriolar vasoconstriction (due to sympathetic NS response to injury;
more about this shortly), followed by histamine mediated...
Local vasodilation to increase local blood flow →bring in nutrients and dilute out
causative agent, and
Increased vascular permeability to increase local tissue fluid volume→to increase
supplies needed to fight causative agent into tissue fluid and to promote healing
Clinical note: occasionally, acute inflammatory vascular responses can be so strong and
the swelling so severe they can cause life threatening manifestations!
e.g. croup (i.e. baby laryngitis) can cause massive laryngeal edema – local response
e.g. anaphylaxis (anaphylactic shock) can cause a dramatic drop in systemic BP, laryngeal
edema and bronchiole constriction – systemic response
2 Minute Review - The Vascular Response
1. What two types of microvascular cells respond to histamine?
_____endothilial cells __________________ and ______smooth muscle cells
_____________________
2. What are the effects of histamine on the microvasculature?
1. a) In arterioles _smooth muscle relaxation -> vaso dialation ____
2. b) In capillaries _______passive vaso dialation increase BP and increase
permeability
3. c) In venules _______myoendothilial contraction and increase vascular
permiabilty – more than capillaries
3. Why is the vascular response important during acute inflammation?
___provide nutrients/dilute destroy causative agents, promote healing
4. What are the clinical manifestations of the vascular response to histamine? _
__the 5 signs _______
5. a) What is actin’s normal function? _____contract cells ________________
b) Which cells express actin? All cells
• Normally: ___muscle cells ___________; During inflammation: ___myo endothelial
__________; • During wound healing: _______anyone _______
Edema: Excess Tissue Fluid
✖Edema
+ Defined as the excessive accumulation of fluid within the interstitial spaces
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+ Aka excess tissue fluid
+ A tissue with excess tissue fluid is called _________?
+ How much excess tissue fluid needs to be present before the swelling
becomes ‘noticeable’? ________
✓What is third spacing? _________________________
✖ Types of edematous fluid
✖ Transudate – plasma that has entered the tissue
✖ Exudate –
A tissue with excess tissue fluid is called
edematous
INTERSTITIAL FLUID = TISSUE FLUID = INTERSTIDIUM
This is a new slide, added to help you understand the concept of edema.
For more information on edema, I suggest your read the section in your text on normal and
altered of water movement.
1st Can. Ed. Chapter 5: p. 115 – 117 and Fig. 5.1 8th Ed. Chapter 3: p. 104 – 108 and Fig. 3.1
7th Ed. Chapter 3: p. 103 – 108 and Fig. 3.1
Not all edema is the same. We will look at the chemical differences between two types of
excess tissue fluid - transudate and exudate.
Normal fluid movement between blood plasma, interstitial fluid, intracellular fluid and
lymph
Note the 4 body fluid compartments!
Look for the 4 pressures that control normal capillary exchange – the movement of
fluid between blood plasma and interstitium by filtration or
reabsorption
2 pressures promote filtration:
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Blood Hydrostatic P (BHP)
Interstitial Fluid Osmotic (oncotic) P
(IFOP)
2 pressures promote reabsorption:
Blood Colloid Osmotic (oncotic) P
(BCOP)
Interstitial Fluid Hydrostatic P (IFHP)
1st Can. Ed.: Fig. 5.1 Normal fluid movement between body fluid compartments
4 body fluid compartments:
• 3 are extracellular, including: 1) blood plasma; 2) interstitial fluid; and 3) lymph; the 4th is the
intracellular fluid compartment. Fluid is constantly moving between these compartments
because nutrient and waste exchange is a constant process.
During normal capillary exchange of nutrients and wastes, there are 4 pressures that control
the net movement of fluids between body fluid compartments:
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2 pressures promote filtration of substances from blood plasma (i.e. intravascular) into
tissue fluid (and then into the body cells) e.g. nutrients and inflammatory chemicals;
2 pressures promote reabsorption of substances from the tissue fluid (and body cells)
into the blood plasma e.g. cellular waste products.
A bit about the 4 pressures:
1) blood hydrostatic pressure (BHP) – water P; promotes filtration - pushes fluid into tissues,
allows nutrients to enter tissues
2) blood colloid osmotic/oncotic pressure (BCOP) – promotes reabsorption - proteins and ions
that exert osmotic P and pull fluid back into the blood (esp. albumin and Na+), normally helps
prevent excess fluid build up in the tissues
3) interstitial fluid hydrostatic pressure (IFHP) – promotes reabsorption - water P that is usually
minimal but can increase dramatically during inflammation (due to edema)
4) interstitial fluid osmotic/oncotic pressure (IFOP) – promotes filtration - usually minimal but
if increased, the extra interstitial proteins exert osmotic P and pull water towards them, thus
promotes increased tissue fluid (edema)
Intracellular osmotic P – is normally equal to blood osmotic P, therefore cells retain normal
morphology
In normal healthy tissue capillary exchange, more fluid is filtered than is reabsorbed. The excess
tissue fluid is quickly drained away by the lymphatic system capillaries. No edema occurs.
Remember, the normal role of the lymphatic system is to pick up excess tissue fluid and return
that fluid (called lymph) to the blood stream.
What are these 4 pressures important? Think about what happens during that acute
inflammatory response. When arterioles vasodilate and the capillary and venule endothelial
cells increase their permeability... they promote filtration. The volume of tissue fluid increases
dramatically. Can the lymphatic drainage keep up with this sudden increase in tissue fluid? Not
always. What happens next? That excess tissue fluid stays in the tissues and edema occurs.
Edematous fluid is more specifically called transudate or exudate. What is the difference in
these terms? Next slide ☺
Transudate vs Exudate
What are Transudate and Exudate?
✖ Terms used to describe the excess tissue fluid produced during an inflammatory
response
✖ Main Differences?
✖ Timing of production
✖ Specific chemistry
The timing and chemistry of the excess tissue fluid is important to its function in the
inflammatory and healing processes. The next slide compares the chemistry of transudate and
exudate.
Why is excess tissue fluid important during inflammation?
Remember, the purpose of inflammation is to dilute out injurious agents and bring in
nourishment as well as WBCs that can hopefully destroy foreign agents. The fluid and debris
within the damaged site will eventually make its way into lymphatic capillaries and ultimately
enter a lymph node or the spleen to be destroyed by various innate and if stimulated by the
specific antigen, adaptive WBCs, thus also promoting wound healing.
Comparison of Transudate
vs. Exudate
Transudate
Exudate – 2 types
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✖ Immediate, excess watery tissue
fluid
✖ Essentially same chemical
composition as normal tissue fluid
produced during capillary exchange
→water, salts, electrolytes
✖ Result of ↑ local blood flow and
↑ local blood hydrostatic P (due to
arteriolar vasodilation)
✖ Most transudate is pushed out of
dilated arterioles; some from
capillaries
✖ Helps dilute out injurious agent
1) Fluid exudate: excess tissue fluid rich in
plasma proteins
+ Proteins help with innate and adaptive
immune responses→contains antibodies,
complement, cytokines to aid in pathogen
destruction and wound healing
2) Cellular exudate: the WBCs that emigrate
into the injury site
+ WBC phagocytosis of causative agent and
cell debris to aid in destroying pathogens and
in wound healing
✖ Most exudate flows out of venules since
they have largest interendothelial cell gaps
and greatest ↑ vascular permeability
Transudate and exudate are simply terms denoting excess tissue fluid – i.e. edema. They allow
for a more detailed analysis of the chemistry of the tissue fluid and the time frame of the
inflammatory response. Transudate occurs immediately following injury; fluid and cellular
exudate takes a bit more time to accumulate in the damaged tissues but is a more nourishing
fluid with some phagocytic WBCs to help destroy pathogens and help clean up the wound site.
Pharmacological note: Since fluid exudate is a blood plasma product, it contains any drugs
administered to the patient. This tissue fluid is constantly being exchanged with blood plasma
either directly or via lymphatic drainage. Any drugs that reach the kidneys or liver will be
metabolized (destroyed) and removed from circulation. For these reasons, therapeutic drugs
such as antibiotics must be administered to the damaged area in a steady dosage to maintain
their therapeutic effects. Patient compliance is important!
Bhp bcop
A. Normal homeostatic pressures across the capillary bed, thus normal homeostatic
intravascular and extravascular fluid balance (notice that the blue and green arrows are the
same size).
Blood Hydrostatic Pressure; BHP is the pressure of the blood plasma within a blood vessel.
Within the microvasculature, BHP is normally highest is arterioles and lowest in venules, so
blood naturally flows in this direction. BHP is a pushing pressure that pushes fluid out of the
capillaries into the interstitium.
Blood Colloid Osmotic Pressure; BCOP is the pressure of the plasma proteins to pull water
towards them. BCOP is a pulling pressure; pulling water towards the chemical exerting osmotic
pressure e.g. albumin in blood plasma (its the most abundant plasma protein).
This slide provides some clinical examples of increased BHP or decreased BCOP as causes of
tissue edema. Let’s look at the clinical significance of changes in blood hydrostatic or blood
colloid osmotic pressures and their effects on the production of excess tissue fluid.
B. Production of transudate:
Edema due to increased Blood Hydrostatic Pressure (BHP):
• E.g. Due to obstruction of venous drainage (venous outflow) e.g. varicose veins. Varicose veins
damage venous valves and cause congestion of blood in the systemic veins which pushes fluid
into the tissues leading to peripheral edema in the legs.


E.g. Due to congestive heart failure. CHF occurs when the heart muscle is too weak to
pump blood effectively. This also causes congestion of blood, especially in veins. Similar
to obstructed venous outflow, that increased venous pressure causes back pressure to
the microvasculature and pushes fluid into the tissues.
E.g. Due to hypertension. Dramatic increase in arterial BP causes increased BHP in the
arterioles and capillaries, thus more fluid is pushed into tissues at the arteriole end of
the capillary bed than can be reabsorbed at venular end of microvasculature.
Edema due to decreased blood colloid osmotic pressure:
• E.g. Liver disease or kidney disease. Your liver makes the majority of your plasma proteins,
including albumin (albumin is a major regulator of water balance in blood plasma; it exerts
blood colloid osmotic pressure which means it pulls water towards it). Hypoalbuminemia
causes a decrease in the osmotic pressure of albumin; transudate fluid stays in the tissues
causing peripheral edema and leading to a decrease in blood volume too. Some kidney
disorders result in a loss of plasma protein into the urine, again leading to peripheral edema.
What happens during acute inflammation? A reminder...
During acute inflammation, due to the rapid histamine mediated vascular response, local
arteriole vasodilation causes increased local blood flow into the injury site. This increases local
capillary BHP. Increased local BHP will push fluid from the blood into the tissues→transudate
forms ... then the endothelial cells contract, increasing venule and capillary vascular
permeability allowing larger proteins and WBCs to enter the interstitium→fluid and then
cellular exudate forms.
Visualizing Transudate and Exudate
✖Transudate – watery
✖Exudate – thicker consistency due to proteins and WBCs
Transudate is the first edematous fluid at an injury site
A visual is always a good choice to add.
What are the types of WBCs and the types of proteins found in exudate? These are our next 2
topics in our study of inflammation: cellular mediation of inflammation and then the plasma
protein systems involved in the inflammatory response.
The next slide shows how transudate and exudate are formed during various clinical situations.
mechanism of edema
Cause of edema
Acute Inflammation
- Lewis’s Triple Response
✖Lewis’s Triple Response
+ Illustrates the vascular responses to tissue injury that occur ...
+ Immediately (within 1 or 2 seconds):
✖ Sympathetic NS stimulated (via NE or epi) →transient local arteriolar
vasoconstriction
✖ Look for a white line which rapidly disappears + Within several seconds:
✖ Histamine stimulated Lewis’s Triple Response
✱ The Flush
✱ The Flare
✱ The Wheal
• When a tissue is injured, two smooth muscle vascular effects occur in very quick succession...
• Arteriolar vasospasm - immediate, but brief vasospasm as smooth muscle contracts in
response to sympathetic NS release of norepinephrine or epinephrine (transient
vasoconstrictive stress response to injury)→white line, followed quickly by
• Arteriolar vasodilation – smooth muscle relaxes in response to release of histamine from
degranulated local mast cells→redness
Let’s look at the acute inflammatory response ‘in action’! This is going to hurt a bit!
1.
2.
3.
4.
5.
You can work alone or with a partner.
Take out your timer.
Choose your longest finger nail.
Use this finger nail to scratch your other forearm.
Watch the dermal vascular responses that occur; take a video if you wish!
Be prepared to answer the questions on the next slide!
Visualizing Lewis’s Triple Response
✖ The vascular response to histamine secretion
+ the FLUSH
✖ Red line – due to local capillary
vasodilation; occurs within seconds (passive ) vasodialation
+ the FLARE
✖ Bright red zone surrounding the red line due to local arteriolar
vasodilation; (active vasodialation ) takes 15 – 20 seconds
+ the WHEAL
✖ Swelling at the site due to fluid shift of intravascular fluid into
tissues, caused by increased vascular permeability of local
venules; takes 1 – 3 minutes
❖The triple response is normally preceded by a transient SNS mediated
vasoconstrictive white line!
3 Major Components of the Acute Inflammatory Response
1. 1) The Vascular Response
2. 2) The Cellular Response
3. 3) Plasma Protein Systems
We will now discuss the major cellular mediators of inflammation.
Mast cells and basophils release histamine, which then initiates a variety of local tissue
responses.
WBCs, platelets and endothelial cells as well as damaged parenchymal cells and any foreign
invaders (e.g. bacteria, viruses) can all release a variety of proinflammatory chemicals that act
as chemotactic agents (‘distress signals’), vasodilators, pain inducers or affect vascular
permeability.
Collectively, these proinflammatory mediators and the 3 plasma protein systems (still to be
discussed) form the acute phase proteins – proteins released during acute inflammatory
responses.
Resources:
1st Can. Ed. Fig. 6.6 lists the principal mediators of inflammatory responses
Handout on Learn: Summary of Cell Mediators of Inflammation has more information and a
review of the WBC subtypes.
The Cellular Response to Acute Inflammation
+ Role of stromal tissue mast cells + Role of peripheral blood cells
✖Role of WBCs (leukocytes; the immune cells)
✖Role of RBCs (erythrocytes)
✖Role of platelets (thrombocytes)
Mechanisms of Defense and Repair
- Inflammation and Wound Healing
Histology – blood smear
This probably looks familiar from your A and P course! You will not
need to remember what they look like histologically, but you do need to know what they do.
Meet your Immune Cell Team!
✖ Promote inflammation:
Basophils &*Mast cells
Secrete HISTAMINE and other proinflammatory
mediators
✖ Act as phagocytes: APC






+ *Neutrophils (PMNs) – 1st responders
+ *Macrophages (monocyte derived)
+ *Dendritic cells
+ B lymphocytes
+ NK cells
+ Eosinophils ✖ also secrete histaminase
(stops histamine effects at end of inflammatory
event)


+ NK cells
+ Eosinophils ✖ also secrete histaminase (stops histamine effects at end of
inflammatory event)
✖ Induce cell apoptosis:



+ NK cells
+ Eosinophils
+ Cytotoxic T lymphocytes
✖ Aided by APCs and Helper T lymphocytes
✖ Boost innate and adaptive responses: + *Helper T cells – boost everybody!
Refer to Handout - The Summary of Cellular Mediators of Inflammation for detailed functions
of each WBC subtype.
*Surveillance cells of the Mononuclear Phagocyte System - immune cells that are in
abundance at body surfaces e.g. dendritic cells within epidermis/dermis, mucous membranes,
various fixed macrophages (that reside in specific tissues) and wandering macrophages that
tour the lymphatic system, blood stream, interstitium and fascial planes - constantly looking for
trouble in the form of foreign antigens; excellent phagocytes. (Macrophages are monocytes
that have left the blood stream and reside and function in a specific tissue or organ; many have
organ specific names e.g. Kupffer cells in the liver, microglia in the brain, dust cells in the lungs).
These cells were discovered at different times by different scientists and named without
knowing their specific functions.
How do WBCs recognize tissue damage? Innate immune cells recognize and react to specific
microbial membrane protein patterns or microbial by-products or even chemicals released by
your own damaged body cells – more about this shortly.
Apoptosis – programmed cell death; part of normal cell physiology - due to lack of use (e.g.
extra uterine smooth muscle cells after the baby is born) or, in the case of the inflammatory
response, targeted cell death due to the release of cytolytic chemicals by various WBCs
APCs = antigen presenting cells – phagocytize, process and present antigen fragments (pieces of
antigen attached to a cell membrane protein called MHC) to cytotoxic T cells of the adaptive
immune system. If the cytotoxic T cell has a receptor that can bind to the antigen (TCR = T cell
receptor), it will bind then attack the APC, thus destroying the antigen – this process is called
cellular mediated immunity.
Development of immune function
We are born with some innate WBCs such as intravascular neutrophils and tissue mast cells but
very few adaptive immune cells. Thus adaptive immune function is minimal at birth, becoming
fully functional by 2 years of age. (even by 1 year of age most children have a fairly robust
immune response to infection; think about the importance of a child’s one year booster shots!)
PMN = polymorphonuclear leukocytes; i.e. neutrophils
*Surveillance cells – innate WBCs located at common sites of entry of pathogens epidermal/dermal and mucosal surfaces; lots of cellular receptors to detect damage/infections
2) The Cellular Response: Stromal Mast Cells
✖ Mast cells are innate immune cells that recognize and respond to tissue ‘distress’
signals by secreting histamine
✖ Mast cell characteristics:
+ Connective tissue (stromal) WBCs related to basophils
+ Produce and secrete many proinflammatory mediators, including histamine and
heparin (anticoagulant)
+ Recognize tissue damage, microbial invasion


✖ How? Lots of cell surface receptors that can bind a variety of chemical
‘distress signals’ →triggers mast cell activation and histamine secretion
✖ Microbial or damaged cell sources: PRRs, PAMPs, DAMPs, and TLRs
Basophils are white blood cells that reside in the blood stream and secrete histamine and
heparin. Basophils are the rarest of all peripheral blood cells.
Mast cells are essentially basophils that left the blood stream and reside in the connective
tissues (stroma) of all organs. Mast cells are stromal surveillance cells with lots of receptors for
microbial and damaged cell chemicals, which are often called ‘distress signals’. When these
chemicals bind to mast cell receptors, mast cells are activated. Activated mast cells secrete
histamine and other proinflammatory mediators→acute inflammatory response occurs.
How do innate immune cells such as mast cells know that tissue damage has occurred? How do
they know that an infective/foreign agent is present?
• All immune cells have membrane receptors that can detect tissue damage or presence of
infectious agents; mast cells (and macrophages and dendritic cells) happen to have lots of these
receptors
Do not memorize which receptors are specific to which WBCs, but here are a few broad
categories:

Pattern recognition receptors (PRRs) – recognize microbial cell surface chemical
patterns



Pattern associated molecular patterns (PAMPs) – recognize products of microbes
Damage associated molecular patterns (DAMPs)- recognize products of body cellular
damage (your body’s own distress signals)
Toll like receptors (TLRs) – recognize a variety of microbial cell wall or surface chemicals
Binding of one of these tissue damage or infective agent chemicals to any of these
receptors triggers the mast cell to respond with the release of proinflammatory
chemical mediators – promote the inflammatory response.
Note: other WBCs also respond to different distress signals e.g. neutrophils, dendritic
cells and macrophages
Mast Cell Responses during Acute Inflammation
Mast cells respond in 2 ways: 1) Mast cell degranulation
+ Process by which mast cells secrete histamine and other pro-inflammatory mediators
in response to tissue damage
Histamine ❖Major chemical mediator of inflammation
✖ Elicits all 5 signs* of the inflammation→stimulates the 3 major components of the
acute inflammatory response: vascular, cellular and plasma protein responses
2) Mast cell synthesis
+ Activated mast cells synthesize many proinflammatory cytokines and
chemokines including interleukins, leukotrienes, prostaglandins and platelet activating
factor
Pro-inflammatory chemical mediators called cytokines or chemokines – promote the
inflammatory response
Interleukins (ILs)
Leukotrienes (LTs)
Prostaglandins (PGs)
Platelet activating factor (PAF)
* Histamine does not directly cause pain. However, because it stimulates the edema that
pushes on nerve endings causing them to be compressed or irritated, it is said to elicit all 5
signs, even if one is an indirect effect.
Visualizing Mast Cell Degranulation
Mast cells store histamine and heparin in tiny,
membrane bound cytoplasmic vesicles. In response to
local
tissue damage, mast cells will secrete histamine. Since
the
histamine is being released from granules that stain dark purple when dyed, release of
histamine makes these granules lighter in appearance. The process of histamine release is
called mast cell degranulation.
Look at the two mast cells in the Figure. The resting mast cell is full of dark purple histamine
containing secretory vesicles. The activated mast cell’s membrane is ‘ruffled’ in appearance due
to the release of histamine via exocytosis (called mast cell degranulation). When a tissue is
injured, the local mast cells will quickly degranulate and release histamine. That histamine will
directly or indirectly stimulate all 5 signs of the inflammatory response.
Mast Cell Degranulation and Synthesis
Mast cells actually produce and
release a lot of different
proinflammatory mediators.
Proinflammatory mediators
include histamine and chemicals
that work in conjunction with histamine to promote or prolong
the inflammatory response. Notice the various functions
highlighted in red boxes.
Fig. 6.7 also has an excellent explanation of the effects of these major pharmacological drugs on
the inflammatory response. Here is a bit of pharmacokinetics...
Prostaglandins (PGs) and leukotrienes (LTs) are important proinflammatory chemical
mediators derived from arachidonic acid. Arachidonic acid is a normal cell membrane
phospholipid that is released to break down into PG and LT, both of which are proinflammatory
distress signals as body cells are injured/killed and their cell membranes are destroyed.



NSAIDs (non-steroidal anti-inflammatory drugs) include aspirin (ASA, acetylsalicylic acid)
and ibuprofen
 NSAIDs block the arachidonic acid→cyclooxygenase pathway. This means that
the production of prostaglandins is decreased which:
 1) decreases vasodilation and vascular permeability→anti-inflammatory effects
that decrease swelling; and
 2) decreases pain signals→analgesic effects
 ASA specifically also blocks thromboxane A2 (TX A2). TX A2 is a platelet release
chemical that promotes platelet plug formation. This is why ASA is also an
anticoagulant.
Acetaminophen (Tylenol) only blocks the pain component of the cyclooxygenase
pathway →PG synthesis pathway, thus does not have anti-inflammatory effects.
Corticosteroids/glucocorticoids such are steroidal drugs that block the production of an
earlier chemical in the pathway – phospholipase A2. Thus, cortisol prevents the
production of both prostaglandins and leukotrienes, making it a potent antiinflammatory. Glucocorticoids also block histamine release. Glucocorticoids are also
steroidal hormones made by the adrenal cortex. Cortisol is a major mediator of the
stress response. More information about cortisol in the stress and disease module.
• Notice the role of antihistamines, too.
2) The Cellular Response: WBCs
WBC Responses during Acute Inflammation
✖ Initiated by: 1) increased vascular permeability causing slower local blood flow
and 2) injured cell distress signals
+ 1) Slow blood flow? allows WBCs to enter plasmatic zone→adhere to
endothelium→WBC
margination/pavementation→diapedesis→emigration→cellular exudate
produced
+ 2) Distress signals? promote WBC chemotaxis into injury site
✖ Functions of WBCs in wound site?
+ Phagocytosis or apoptosis of pathogens and cell debris →destroy pathogens and
promote healing☺
✓Name the first responders _________________
During acute inflammation, all three blood cell types will be affected by the change in blood
flow. As fluid leaks out of the blood stream and the blood viscosity in the area increases, the
local rate of blood flow slows down. Slower flow allows time for the blood cells to enter the
plasmatic zone, adhere to the endothelium and then enter the damage site and help in the
inflammatory response. We will now discuss how plasma WBCs respond to local tissue damage
and enter the wound site.
Phagocytosis


Ingestion and enzymatic and/or peroxide digestion of cell debris, foreign material,
microbes
Aids inflammatory response by remove causative agents and debris which promote
wound healing
Apoptosis
• Programmed cell death via the use of cytolytic (cell destroying) chemicals such as granzymes
and perforins
Read about the process of phagocytosis in your textbook.
Review phagocytosis using Fig. 6.9 (1st Can. Ed.) or Figure 7.15 (8th or 7th Ed.) from your text
and by watching the video link posted on Learn.
A. WBC Emigration into wound site is mediated by Chemotaxis:
• WBCs, especially neutrophils, respond immediately to a chemical trail of ‘distress signals’ from
damaged tissues Chemotaxis


The directional movement of leukocytes in response to a chemical gradient
Common chemotactic agents: cell debris, microbes, proinflammatory chemicals
• Note: some books call these chemicals chemoattractant
Margination (aka Pavementation) is the movement of WBCs into the plasmatic zone of the
vessel. WBC margination is followed by adherence to endothelium via cell adhesion molecules
(CAMS)

Mechanism by which WBCs move to outer margins of vessel, ‘roll’ (tumble) along the
endothelium, adhere to
endothelium (by binding to endothelial cell adhesion molecules made only during
inflammatory response)

WBCs then squeeze through the interendothelial gaps between adjacent venular
endothelial cells (remember
that myoendothelial cell contraction?) and enter into the wound site, a process called
diapedesis. Diapedesis
• Mechanism by which WBC squeeze into wound site; an amoeboid movement (flowing of
cytoplasm against cell membrane)
Emigration
• The actual movement of the WBCs from the intravascular to the extravascular space (i.e. into
the wound site); they follow the chemotactic trail right to the damage!
Entire process takes about 10 minutes!
B. Recognition and attachment of WBC to microbial chemicals of bacterium
CAMS = cell adhesion molecules made by phagocytes in response to microbial chemicals or
damaged cell products; help with phagocytosis of the correct cell (i.e. those that should be
‘eaten’ in the wound site. Notice that some of these adhesion molecules are the cellular
receptors WBC use to recognize microbial or body cell chemicals: PRRs and PAMPs. Other
foreign proteins (antigens; Ag), and microbial proteins attached to antibodies (Ab) as well as
some complement proteins (C3b) also stimulate phagocytic cells to adhere to and then ingest
the cells/chemicals that need to be removed from the wound site.
C. The steps involved in phagocytosis
Fig. 6.9 A enlarged Read the caption under this figure in your
text and look for: Adherence, margination and diapedesis
1. 1) WBC adherence to endothelial cells (notice the
endothelial cell ‘contraction’ (aka retraction)
2. 2) WBC margination/pavementation →begin diapedesis →emigration into wound
site
3. 3) Diapedesis continues →WBC emigration into wound site
Chemotaxis, infiltration/emigration and phagocytosis
1. 1) Chemotaxis – positive chemotaxis as WBCs follow the chemotactic trail towards the
wound site
2. 2) Lots of WBCS (neutrophils here) have migrated/infiltrated the wound site
3. 3) Phagocytosis occurs
Leukocyte emigration (aka leukocyte infiltration) is the movement of WBCs from the blood
into the damaged tissue site. This directional movement is controlled by chemotactic agents,
‘distress signals’ released by damaged cells, including damaged vascular endothelial cells,
damaged parenchymal cells as well as by the presence of microbial chemicals. Since the WBCs
move toward the chemotactic agents, this process is sometimes called positive chemotaxis. The
WBCs are essentially blood hounds that follow the chemical scent to the damage site.
Neutrophils seem to have the best ‘noses’ to scent out the distress chemicals. Usually the first
WBCs to emigrate into the wound (and since they compose ~ 60% of all circulating WBCs in the
peripheral blood stream), they arrive in large numbers. They also have very short life spans
(often only minutes) in the wound site () and often become distress signals themselves.
Common chemotactic agents include:
• Dead and dying body cell chemicals; proinflammatory chemicals released during
inflammation, including components of the complement system (part of innate immunity)
(especially proinflammatory C5a and C3a); Leukotrienes (LTs) – proinflammatory products of
the lipoxygenase pathway of arachidonic acid metabolism synthesized by activated mast cells
and also released by other cells if their cell membranes are damaged.
Phagocytosis vs Apoptosis
✖Two ways to destroy a foreign invader!
First video – phagocytosis in action - watch a WBC engulf a bacteria!
Second video – apoptosis – watch as WBC releases cytolytic enzymes that damage cell
membranes of targeted cells (pathogens and damaged body cells) and ultimately destroy the
targeted cell.
Apoptosis is used by innate NK cells and adaptive cytotoxic T cells (Tc cells/CD8 cells) and
eosinophils.



NK cells kill pathogenic cells and damaged body cells.
Tc cells specifically kill other WBCs that have previously phagocytized and processed
antigens into small fragments that are ‘displayed on the outer cell membrane of the
phagocytic WBC. Now called antigen presenting cells (APCs), Tc cells bind to the antigen
fragments, secrete cytolytic enzymes and destroy the entire APC.
Eosinophils kill parasites. Eosinophils also phagocytize and destroy antigen- antibody
complexes
Unsuccessful Phagocytosis
Tonsillar pustules due to Streptococchal throat infection
1. In some people, macrophages living in tonsils become
breeding grounds for bacteria such as pustule forming
Streptococchus. Tonsils will need to be removed to
prevent opportunistic infections
2. Post-tonsillectomy
What happens if phagocytosis is not successful and in fact,
macrophages become a breeding ground for chronic
infection/inflammation?
Example: repeated strep throat infections leading to chronic tonsillitis
2) The Cellular Response: Platelets
Platelet Response during Acute Inflammation

Platelets respond to:
 1) abnormally slow/viscous blood flow →resulting from increased
vascular permeability during inflammatory response; and/or

2) loss of endothelial cells due to blood vessel wall damage→allows
platelet-collagen interaction

Platelet activation includes:
• Platelet adherence →platelet release reaction →platelet plug formation
→hemostasis
❖Purpose of platelet activation? Initiate hemostasis to prevent further blood
loss
Platelets also notice the vascular response to tissue damage, especially the slower, more
viscous blood flow as intravascular fluid enters the damaged tissue. If endothelial cells are
destroyed by the cause of the injury (are you bleeding?), platelets will interact with the normal
CT protein collagen. Abnormally slow blood flow and/or collagen interaction are the two signals
that will cause platelet activation.
Hemostasis: defined as the stoppage of blood flow (to prevent excessive bleeding)
• Activated platelets will try to plug the lesion in the blood vessel; if they aren’t successful, they
will trigger a blood clot to form (in a process called the coagulation cascade)
Platelets (thrombocytes) are the blood cells that initiate formation of a thrombus (if
intravascular) or blood clot (if extravascular).
Components of a thrombus or blood clot? Platelets, sticky fibrin threads and trapped RBCs
(Note: We will review hemostasis (the coagulation of blood) briefly in the last step in the acute
inflammatory response: 3) plasma protein systems, coming up next!)
Platelets travelling through the wound site microvasculature notice the slower blood flow rate
and begin to leave the axial zone and enter the plasmatic zone. This means that these platelets
come in contact with the wounded endothelial lining of the vessel and the CT components in
the underlying tissues.
Platelets become activated when they come in contact with a connective tissue protein called
collagen. Since collagen is a ubiquitous connective tissue component located directly outside of
the endothelium, platelet-collagen interaction in a damaged vessel is expected. Activated
platelets stimulate blood clot formation. Since tissue damage often includes damage to blood
vessels and bleeding, blood clot formation is an important part of the acute inflammatory
response!
Clinical significance?
Patients suffering from thrombocytopenia bleed longer; those with thrombocytosis are prone
to dangerous intravascular thrombotic events.
Platelet Activation during Hemostasis
•Platelet Plug Formation is a 3 stage process:
Platelet formation
Remember your blood vessel anatomy?
All blood vessels are lined with endothelial cells (tunica intima) – the yellow cells in this figure.
Regardless of the size of the blood vessel, directly beneath the intimal endothelium, there will
always be connective tissue and that means there will always be the protein, collagen.
Result? Anything that damages the endothelial lining of any vessel will stimulate plateletcollagen interaction. The platelets will always respond by adhering to the region, releasing
various pro-thrombotic chemicals that make the platelets enlarge, become sticky and begin to
aggregate at the endothelial wound site.
Platelet Plug Formation:
1) Platelet adhesion - damage to endothelial lining→platelets contact collagen→platelets
enlarge and change shape; become ‘sticky’→adhere to vessel wall endothelium
(2) Platelet Release Reaction

Platelets secrete prothrombotic chemicals that make them enlarge and
become ‘sticky’ including PDGF, Serotonin, Thromboxane A2, ADP

Pharmacology note: ASA is an anticoagulant because it blocks thromboxane A2
synthesis
(3) Platelet Aggregation
• Platelets may successfully plug the wound and stop the bleeding by forming a platelet plug
Still bleeding? Now you need the clotting cascade
2) The Cellular Response: RBCs
RBC Response during Acute Inflammation





RBCs respond to:
 1) slower local blood flow→resulting from increased vascular permeability
during inflammatory response; and/or
 2) platelet activation
RBC activation includes:
 RBC adherence→Rouleaux formation→followed by extravasation
→RBCs help form extravascular blood clot
 Purpose of RBC response? Help limit blood loss by strengthening
and stabilizing a blood clot
During the acute inflammatory response, local plasma is entering the wound site,
causing the blood remaining in the local microvasculature to thicken a bit. This slower,
thicker blood flow in combination with a potential open wound in the vessel and
increased venule permeability all promote RBCs traveling within the damaged part of
the vessel to begin to stack up and then spill out of the vessel. Rouleaux is the stacking
up process (think of a stack of rolo chocolates!). Extravasation is the process of blood
cells leaving a blood vessel (extra = outside; vaso = vessel)
Extravasated RBCs will be trapped by the proteinaceous clotting fibers called fibrin
threads and become part of the thrombus. Extravasated RBCs form bruises and
hematomas.
Rouleaux Formation by RBCs
•Can you see the neutrophils adhering to endothelial cell
adhesion molecules (boxed area) and then using
diapedesis to emigrate from the capillary into the wound
site? (They also use venule gaps to emigrate). The inset
figure illustrates adhesion of a neutrophil. Notice that
platelets also adhere to endothelial cell adhesion
molecules. Lots of WBCs use diapedesis to squeeze
through the gaps between adjacent endothelial cells.



•Can you see the platelets and RBCs adhering to endothelial cell adhesion molecules?
The platelets will be activated to form the platelet plug by aggregating at the site of
damaged endothelium. If RBCs are spilling out of the damaged vessel in a process called
extravasation, then the person is bleeding and the coagulation cascade needs to be
initiated.
Finally, notice the fibrin deposition. Fibrin is the major blood clotting fiber. We will
discuss fibrin production in the next section on plasma protein systems, specifically
coagulation.
Visualizing the Blood Cell Responses to Vasodilation and Increased Vascular
Permeability
Each arrow corresponds to a specific cellular response
that occurs during the vascular inflammatory response:
1.
2.
3.
4.
Platelet aggregation begins the thrombotic process; RBCs starting to accumulate, too.
Margination - WBC moving towards endothelial cell lining of blood vessel
Pavementation of WBCs along endothelium
Nucleus of endothelial cell lining the vessel – WBCs must emigrate through gaps
between the endothelial cells that have undergone myoendothelial ‘contraction’
5. Fluid exudate (white spaces) within the edematous tissues. Cellular exudate will follow
as the WBCs squeeze through the interendothelial gaps and enter the wounded tissue
site.
3 Major Components of the Acute Inflammatory Response
1. 1) The Vascular Response
2. 2) The Cellular Response
3. 3) Plasma Protein Systems
 Complement system
 Clotting (coagulation) system
 Kinin system
We will discuss 3 plasma proteins systems that are part of the innate immune system. These
are cascades of plasma proteins that become activated in a particular sequence, during tissue
damage. The activation of these plasma proteins is interrelated, meaning that activation of a
protein in one system may trigger activation of a protein in a different plasma protein system.
Most of these plasma proteins are made in advance by the liver and circulate in the blood
plasma in an inactive precursor form called a proenzyme. Most are enzymes which catalyze
(speed up) a chemical reaction of that is involved in promoting the inflammatory response i.e.
they are proinflammatory chemical mediators.
3) Plasma Protein Systems
▪What are the plasma protein systems?
▪3 interrelated groups of proinflammatory plasma proteins →activated by tissue
damage →cascade or domino effect
▪aka Acute Phase Proteins:



The complement system
The clotting (coagulation) system
The kinin system
• Part of fluid and cellular exudate
• Part of the inflammatory soup
The plasma protein system is activated during the acute inflammatory response.
You may remember that the fluid exudate includes transudate plus proteins. Thus, fluid
exudate includes the proteins of the 3 plasma protein systems.
These proteins would still be present in cellular exudate. We will briefly discuss each plasma
protein system and their role(s) in the inflammatory response to tissue damage.
Clinical note: All proteins are produced when specific genes are turned on (expressed) and
protein synthesis occurs. If one or more proteins within a particular plasma protein system is
not present or is in short supply; that entire aspect of the inflammatory response will be
lessened or even absent. The dominoes stop falling down and the effect is not completed. This
could occur if the gene that codes for that protein is not functioning (e.g. some blood clotting
disorders). Alternatively, overexpression of one of these genes could cause overproduction of a
particular protein which could cause exaggeration of that particular plasma protein pathway
possibly leading too much of a particular inflammatory response.
❖You may find it helpful to read this section of your text.
3) Plasma Protein Systems
✖General Characteristics




▪ Produced by liver and/or WBCs
▪ Most produced in advance; circulate in blood plasma as
inactive proenzymes
▪ Peak activity 10 – 40 hours post tissue damage
▪How do they work? Mechanism of activation
▪When tissue damage occurs→inactive circulating
proenzymes→convert to active enzymes→cascade of enzyme
activation
→promote inflammatory response
▪Act as proinflammatory mediators
▪Support and maintain the histamine response
▪Help prevent further blood loss
▪Need more of them?
▪1) WBCs release cytokines (e.g. interleukins – IL-1 or IL-2)→stimulate liver to
produce more and/or
▪2) produced in situ by damaged body cells
Most of the acute phase plasma proteins are made by the liver or in WBCs in advance and
circulate in the blood plasma in an inactive form, often as proenzymes. This prevents
unnecessary, potentially harmful enzymatic activation within healthy tissues such as the liver
cells or WBCs in which they are produced.
Tissue damage will initiate the enzymatic activity of one or more components of a particular
system (inactive proenzyme to active enzyme). Once the first protein is activated, a domino
effect occurs, resulting in the activation of the remaining proteins of that system - producing a
cascade effect.
These activated plasma proteins are enzymes called proteases (enzymes that change the
structure of other proteins) that have complex overlapping roles.
Each plasma protein system stimulates some aspect of the inflammatory response. You will see
that they often have overlapping functions – a bit of a safety net to ensure that the
inflammatory response is successful.
Cytokines: part of innate immune system; paracrine and autocrine hormones made by WBCs;
act as communication signals between WBCs; secreted to alert immune system to presence of
tissue damage to help promote the inflammatory response. Interleukins are common used
cytokines (e.g. IL-1 is interleukin-1, IL-2 is interleukin-2 – both are used in adaptive immune
activation of T or B cells, respectively).
3 Plasma Protein
Systems involved in
Inflammation
Complement system
Clotting system
Kinin system
Many of these acute phase plasma proteins are used diagnostically as inflammatory markers.
Since they stimulate inflammation, they are tightly regulated by homeostatic mechanisms.
The Complement System
✖The Complement System
+ Innate immune response (2nd line of defense)
+ Series of 9 plasma proteins; called C1 – C9
+ Source: liver
+ Mechanism of activation:
✖ 3 pathways of complement protein activation:
1. 1) Classical pathway – antibody present
2. 2) Lectin pathway – bacteria present
3. 3) Alternative pathway – bacteria or yeast present
✖ If inactive proenzyme: C1, C3
✖ If active functional enzyme: C1a, C3a, C3b
3 pathways of complement activation:
1. 1) Classical pathway – C1 activated by presence of antibodies (Ab)
2. 2) Lectin pathway – C1 activated by bacterial polysaccharides (mannose); does not need
Ab
3. 3) Alternative pathway – C3 activated by bacterial lipopolysacharides (LPS) or yeast
carbohydrates; does not need Ab
Note: How to determine if a complement protein is an inactive proenzyme or an activated
enzyme?


C1 – C9 means the complement protein is inactive
C1a – C9a means this protein is now active and triggering activation of the next
complement protein in the pathway

C3a and C3b are both active complement proteins
Functions of the Complement System
✖Physiological effects of complement protein activation:





+ Form membrane attack complexes (MAC); C5b-C9
+ Act as opsonins (opsonization); C3b
+ Act as leukocyte chemotactic agents - attract phagocytes to site and thus
promote phagocytosis; C5a
+ Act as anaphylatoxins - stimulate mast cell degranulation→histamine release;
C3a or C5a
+ Attract antibodies to wound site; C1a
✖ End result of complement activation? Promote inflammation and help
destroy pathogens
Physiological Effects of Complement Protein Activation:



Membrane attack complex,MAC – C5b-C9: I like to call this a ’Big MAC attack’ –
Complement protein complex pokes a hole in the outer cell membrane of the bacterium
leading to cytolysis e.g. makes bacterial walls leaky to water →bacteria lysed; contents
leak out, bacterium dies (as shown in this figure)
Opsonization – C3b: ‘to make tasty’ this complement protein will ‘sugar’ coat the
surface of the antigen to be phagocytized helping to make the process of phagocytosis
more efficient
Chemotactic agents and anaphylatoxins – C3a and C5a: attract phagocytic WBCs to
damage site and stimulate rapid mast cell degranulation causing histamine release.
Histamine stimulates inflammatory response (named due to link between massive
histamine release and anaphylaxis during a severe allergic reaction).
The Proinflammatory Effects of Complement System Activation
Two representations of the proinflammatory effects of complement activation. Imagine all the
cellular cytoplasmic contents of the target cell leaking out as the MAC pokes holes in it.
In the first figure, notice that all 3 pathways for complement system activation end up aiding in
the destruction of the pathogen.
Having 3 pathways allows a bit of a safety net for our innate immune system – if 1 pathway
doesn’t work or is missing a complement protein, maybe another pathway will be able to
destroy the antigen.
Lack of one or more complement protein or overzealous production of complement proteins
may cause abnormal inflammatory responses.
The Clotting (Coagulation) System
✖The Coagulation (Blood Clotting) System
+ Group of 12 plasma proteins (Factors I–XIII); active Xa ✖ aka clotting factors
+ Sources: liver (major) and as required by platelets or other damaged cells
+ Mechanism of activation:
1. 1) Endothelial damage occurs→platelet-collagen
interaction in damaged blood vessel→platelet activation
2. 2) Blood flow stasis →platelet activation
✖ Platelet activation leads to sequential activation of clotting
factors of the coagulation cascade →sticky fibrin threads form
✱ RBCs and platelets trapped in sticky fibrinous mesh→ blood clot forms
+ End result of clotting factor activation? ✖ Hemostasis to stop the bleeding
Hemostasis is the stoppage of blood flow; i.e. stop the bleeding
The clotting or coagulation system is made of a group of 12 different plasma proteins.
The clotting system is part of the process called hemostasis. Hemostasis is defined as the
stoppage of blood flow.
Why is hemostasis, including the clotting system, involved during acute inflammation?
Tissue injury often involves damage to the blood vessels in the area (think of every bruise or cut
you’ve ever had).
When a blood vessel is damaged, RBCs start to spill out of the vessel (that’s called
extravasation). The process of hemostasis occurs to try to prevent excessive blood loss.
2 Routes to Activation of the Clotting Cascade
1) Extrinsic Pathway


More common
pathway
Damaged body cells
(i.e. tissue trauma
outside of vessel)
→tissue factor III
→Xa
→Common
Pathway of
Coagulation
2) Intrinsic
Pathway



Damage occurs to
blood vessel wall
Platelets, Factor XII
contact collagen
XII →XIIa →Xa
→Common
Pathway of
Coagulation
Common Pathway of
Coagulation:
Xa→Prothrombin
II→Thrombin IIa
Thrombin
Fibrinogen I →Sticky
Fibrin Threads
→Blood Clot
Extrinsic pathway→tissue damage to any parenchymal or stromal cell→ tissue factor
activated→coagulation cascade triggered
Intrinsic pathway →endothelial cell damage →Factor XII activated →coagulation
cascade triggered
Notice that whether the damage was extrinsic – i.e. from the outside and through a vessel wall
(more common) or due to intrinsic damage to the actual vessel endothelial cell lining itself,
both pathways of clotting factor activation meet at the
common pathway of coagulation, initiated by activated Factor X and ending with the
conversion of the inactive soluble plasma protein fibrinogen (a proenzyme) to active, insoluble
fibrin threads. Fibrin threads form the sticky meshwork of a blood clot. Platelets and RBCs stick
to the meshwork, creating a larger plug to hopefully finally stop the bleeding Remember that
endothelial damage allows platelets and CT collagen to interact. Since the endothelial cells line
blood vessels, damage to them implies a hole in the vessel wall – hence the person is bleeding
and needs their blood to clot! Since the collagen is in the underlying tissue connective tissue,
platelet- collagen or Factor XII–collagen interactions should be guaranteed.
Factor XII = Hageman Factor: XII denotes inactive clotting factor; XIIa denotes the active clotting
factor
Cofactors required for blood clotting include Ca2+ and vitamin K
The coagulation cascade is a positive feedback system, since the clotting mechanisms will
continue until either the bleeding has stopped or the supply of clotting proteins is exhausted.
Blood clotting disorders are often the result of an inability to produce one or more biologically
active clotting factors. A common inherited form of hemophilia is due to a genetic defect in the
production of Factor VIII.
Dietary or nutrient absorption issues with calcium or decreased liver production of vitamin K
can also impede normal blood clotting times.
In the cardiovascular unit, we will expand on the causes of intrinsic endothelial damage Hint:
hypertension damages artery walls
Factor 1 ,2 ,3 , 10 , 12 kinda know these clotting factors
Every A and P textbook has a list of clotting factors. Their number corresponds to the order in
which they were discovered. Notice that fibrinogen (the last factor to be activated but the one
most obvious in the clotting pathway) is factor I, fibrinogen.
Don’t memorize all of them for Pathophysiology 1 – you will learn them in Pharmacology. For
this course, look for the roles of activated Factor X, Factor XII and Factors IV (which is calcium),
III, II and I.
Components of a Blood Clot or Thrombus
1 platelets , 2 fibrin threads – acute red blood cells --- cellular exudate
Is it a thrombus or a blood clot?
Thrombus: denotes intravascular blood coagulation
Blood clot: denotes extravascular blood coagulation e.g. bruise, hematoma, contusion
Label the 3 main components of the blood clot!
1.platelets
2.fibrin
3. Acute red blood cells
Name the trigger that starts the cascade. ____________________________
Since a blood clot includes sticky insoluble fibrin threads, plus platelets and red blood cells,
within the wounded tissue, the blood clot would form part of the
___________________________ transudate/fluid exudate/cellular exudate (choose one)
Where are the WBCs? In the wound trying to destroy microbes and prevent more damage.
The Clotting (Coagulation) Cascade
Physiological Effects of the Clotting Cascade
Functions of Blood Clots:
1. 1) Plug damaged vessels to stop further bleeding
2. 2) Trap microbes to prevent the spread of infection
3. Trap microbes and other debris
4. 3) Provide a framework for wound healing
Fibrinous network – a mesh-like collection of sticky fibrin threads
Notice that some of the clotting system purposes overlap those of the acute inflammatory
response in general.
Did you know?



The colours of a bruise (or hematoma) correspond to the breakdown of the hemoglobin
in the extravasated RBCs as they are phagocytized by macrophages. The colour changes
you see indicate that healing is occurring.
Black→blue→green→yellow→back to normal
Once wound healing is complete and the damaged blood vessels have a new, intact
endothelium, another enzyme called plasmin will dissolve the blood clot by breaking up
the fibrin threads. Local tissue macrophages will chew up the clot components that
were trapped within the tissue cells.
The Kinin System
The Kinin System




+ Group of 4 plasma proteins
+ Source: liver (major) and many other body cells
+ Mechanism of Activation: tissue damage
✖ Prekallikrein activated by Factor XIIa of clotting
cascade(!)→→→bradykinin
+ Physiological Effects of Kinins:
✖ Bradykinin has similar, but less potent effects than histamine
✱ Arteriole vasodilation and ↑ vascular permeability→edema, redness,
heat
✱ Acts as chemotactic agent for WBCs
✖ Pain stimulant (works with prostaglandins to irritate nerve endings)





+ End result of kinin activation? Help maintain inflammatory response
Factor XII: aka Hageman factor or prekallikrein activator
The clotting cascade and the kinin cascade have interrelated functions. Why? If an
inflammatory response is occurring, chances are that a blood vessel is also damaged and
some bleeding is present.
Can you see the similarity to some of histamine’s effects? Bradykinin stimulates vascular
smooth muscle relaxation and myoendothelial cell contraction
✓Which kinin function is different from histamine? ____________________
The Kinin Cascade

The Kinin cascade is activated by Factor XIIa
of the clotting system and helps sustain
histamine’s proinflammatory response and
stimulates nerve endings eliciting pain
Fig. 6.4 (missing the complement system part)
So, another name for activated Hageman Factor XII, XIIa of
the clotting cascade is prekallikrein (activator). Prekallikrein
is the enzyme that stimulates the production of bradykinin.
Bradykinin helps histamine sustain the inflammatory
response. This chemical has two names because different
medical researches at different times were studying its
effects on two different proinflammatory pathways.
Some secretions contain kallikreins that can help mediate local inflammatory responses. e.g.
tears, sweat, saliva, urine and feces
Regulation of the Plasma Protein Systems
An inflammatory response is a necessary part of tissue healing after injury, but the level of
response must reflect the extent of tissue damage.
The inflammatory response is very carefully regulated by biochemical mediators
that can activate or inactivate one or more of the 3 plasma protein systems. Since inflammation
is vital to survival, activation of one system often is the trigger to activation of another system.
Tissues do not stay acutely inflamed forever; signals must be present to turn off the proinflammatory histamine, complement and kinins and to release the trapped RBCs and platelets
as the fibrin threads are dissolved.
Proteolytic enzymes that regulate the inflammatory response include:



Carboxypeptidase - inactivates anaphylatoxic C3a and C5a
Kinase – inactivates kinins
Plasmin – limits size of clot and involved in clot dissolution (fibrinolysis, the destruction
of blood clots). Thrombin activates both two proenzymes: fibrinogen →fibrin to stabilize
the clots and plasminogen→plasmin to destroy the clot! Plasmin destroys the sticky
fibrin threads that trap platelets and RBC within a clot. Plasmin also activates C1, C3 and
C5 of the complement cascade and Factor XII of the clotting system to then activate
prekallikrein→initiates kinin cascade. Why?
What if the inflammatory response ended too soon? Then plasmin could trigger a longer
inflammatory response.







Histaminase - made by eosinophils that enter the wound site; inactivates histamine at
end of inflammatory response
Antihistamines are histamine antagonists that block histamine binding to its receptor
are drugs also decrease inflammatory responses.
The Inflammatory Soup
✖Inflammatory soup contains ALL chemical mediators found in fluid
and/or cellular exudate that promote inflammation; including...
Plasma-derived mediators
Cell-derived mediators
This is a clear broth; fluid only, no solids!

Refer to the handout – Summary of Cell Mediators of Inflammation and look at the list of
secretions made by WBCs, platelets and endothelial cells plus those made by the liver and
damaged cells and add them to the list.
The plasma derived plasma proteins are sometimes called the acute phase proteins because
they are activated during acute inflammatory responses.
What’s in the soup?
1) Plasma derived mediators:


Includes the 3 plasma protein systems: complement, clotting and kinin
Recall that these proteins are made in advance by liver and/or WBCs and circulate in
inactive form→activated by tissue damage
❖Another inflammatory marker that is beginning to be used diagnostically is C
Reactive Protein(CRP). CRP is another acute phase plasma protein made by the liver. It
is considered a general indicator of inflammation. You will hear more about CRP in other
courses such as pharmacology
2) Cellular derived mediators: local paracrine or autocrine effects





Made by a variety of cell types: WBCs, platelets, endothelial cells and/or injured cells
Activated by tissue damage
Includes cytokines and chemokines
• Note: cellular derived means chemicals made by cells, not the cells themselves
All proinflammatory mediators may become part of the fluid exudate during the
inflammatory response.
CYTOKINE STORM inflammation can overwhelm the tissues causing extensive tissue
damage When the damaged tissues and the immune system creates too many
cytokines and chemokines inflammation can overwhelm the tissues causing extensive
tissue damage
e.g. covid-19 and lung damage
I would be remiss in a Pathophysiology course if I did not mention a significant complication of
Covid-19 infection – the damage caused by a cytokine storm. Remember these are
proinflammatory chemicals.
Mediators of inflammation
Summary of the chemical mediators found
in the inflammatory soup – a lot of
chemicals are released during inflammation!
Fig 7.9 lists all the principal chemical
mediators and their major roles during the
inflammatory response. You will notice that
they have many overlapping roles.
This is a big list! Look for the key categories
and familiar chemical mediators.
Systemic effects such as leukocytosis
(increased production of leukocytes) occurs during prolonged inflammatory responses, such as
those in chronic inflammatory sites. We will discuss it with chronic inflammation.
ASA pharmacology of ASA –
anticoagulant analgesic ainti-inflamatory
Glucocorticoids – good anti inflammatory – blocks arachidonic acid at higher levels –
blocks more things
Asa- block the ability of arachidonic acid – decrease swelling -Local and Systemic
Clinical Manifestations of Acute Inflammation
Local Manifestations of Acute Inflammation
✖Local Manifestations of Acute Inflammation


+ Extent will depend on severity of tissue damage
+ 5 cardinal signs of inflammation should be present to some degree
✖ Tissue is red, warm to the touch, may be swollen, painful and may exhibit
decreased function

+ Type of fluid or cellular exudate present depends on location and cause of
damage
1. 1) Serous exudate









2. 2) Fibrinous exudate
3. 3) Purulent exudate
4. 4) Hemorrhagic exudate
Types of Local Inflammatory Exudate
✖ Several Types of Local Inflammatory Exudate
Exudate can have different chemical composition and consistency
1. Serous Exudate (Inflammation)
Thin, watery fluid, similar to transudate
1. Fibrinous Exudate (Inflammation)
Contains lots of proteins, thick/viscous
1. Purulent (Suppurative) Exudate (Inflammation)
Contains pus; abscesses or cysts may be present
1. Hemorrhagic Exudate (Inflammation)
Bleeding occurred; contains gel-like coagulated blood

Be able to define each subtype of inflammatory exudate
Note that some authors use the terms exudate and inflammation interchangeably in
labeling these types of inflammatory responses.
Terminology:
Serous = thin, watery secretion that is chemically similar to transudate (minimal
protein)
Fibrinous = contains lots of protein
Purulent/suppurative – contains pus i.e. contains
_________________________________________
Hemorrhagic – contains a blood clot

Serous Exudate: thin and watery


Serous exudate
A. Characterized by the copious effusion (excess tissue fluid accumulation) of nonviscous serous (watery) fluid with very little protein – i.e. transudate.
Found in early inflammatory response or in a mild injury such as a blister (as in A on this
slide)
Consistency varies - watery e.g. blister or may contain thin mucous e.g. runny nose







B. Pleurisy causing serous fluid buildup in the pleural cavity led to right lung collapse
(atelectasis), indicated at arrow. Left lung is visible and still inflated.
Pleurisy is inflammation of the pleural membranes that surround each lung.
Fibrinous Exudate: thick/viscous
Fibrinous exudate means that a large amount of protein is present in the exudate. Fibrin is
commonly located in this type of exudate (hence the name)
This exudate occurs with more severe injury resulting in a large increase in vascular
permeability that allows plasma proteins to pass through the large interendothelial cell gaps in
blood vessels and subsequently deposit in the tissues.
Since fibrin is the protein that creates our clotting fibers, excess sticky fibrin creates a
coagulated (gelled) exudate that covers the surface of the area such as a body cavity e.g.
pericarditis (A), pleurisy, pneumonia or peritonitis (B).
Clinical significance?
Body cavities are surrounded by serous membrane that secretes a clear, thin watery, lubricating
serous fluid not a thicker, more viscous sticky exudate. Fibrinous exudate impairs the normal
ability of organs within body cavities to move freely as they function. For example, in
pericarditis above, the heart’s ability to pump effectively could be severely impaired, leading to
a possible diagnosis of pericardial effusion or cardiac tamponade.
Terminology:
serous = thin, watery secretion e.g. serous fluid in body cavities and serous exudate
during inflammation
Fibrinous = contains the protein called fibrin, clotting fibers
Fibrous = contains the protein called collagen – used with scar tissue formation
Purulent (Suppurative) Exudate
What are pustules? _____areas filled pus____
✓Components of pus 3 of them? White blood cells , tissue cells, bacterium
✓What is the term for removal of purulent exudate? ___evacuate it _____
Purulent (aka suppurating) lesions contain pus.
More tonsillitis!



Composition of pus:
 Pus is a thick, creamy white or greenish fluid
 Pus consists of dead and dying neutrophils, dead and dying body cells, dead and
dying bacteria and tissue fluid
Pus forming bacteria are called pyogenic bacteria e.g. Staphylococchus
Pus may become walled off in a cyst or abscess that must be evacuated
(cleaned/removed) in order for wound healing to occur
Hemorrhagic Exudate
Hemorrhagic exudate means that blood vessels have ruptured, bleeding has occurred and a
blood clot is present.
Hemorrhagic exudate contains extravasated blood cells and clotting factors Platelets, RBCs and
fibrin present; blood clot forms
clinical manifestations of inflammation – effects on
lymphatic system
Lymphadenopathy- enlarged lymph nodes – palpable swelling of 1 or more lymph nodes with
little or no tenderness or pain
, lymphadenitis- panful , inflamed lymphadenopathy enlarged lymph nodes usually due to
infection
, lymphangitis – inflammation of the lymphatic vessels due to infectious or non infectious
causes follows direction of lymphatic drainage
Systemic Manifestations of Acute Inflammation
✖Systemic Manifestations indicate that the tissue damage (e.g. infection) is
spreading to other body regions
Major Systemic Manifestations:
1. 1) Fever (pyrexia) – pyrogens present
2. 2) Leukocytosis - ↑ WBC count
3. 3) Increased acute phase reactant proteins (i.e. ______ ______ systems)
made by liver
4. 4) Increased CRP – diagnostic tool
5. 5) May also include:
o + Malaise, drowsiness and poor appetite
o + Increased liver production of fibrinogen
o + Decreased liver production of albumin
o + Hypotension d/t _________________
We will discuss fever and leukocytosis in a bit more detail in the next few slides.
Leukocytosis: increased number of WBCs – noted in WBC counts; diagnostically, use diff WBC
to determine specific subtypes that are elevated e.g. neutrophils = acute inflammation;
monocytes = chronic inflammation; lymphocytes = viral infection; eosinophils = parasitic
infection
Hypotension: low blood pressure due to? ______________________
Acute phase reactant proteins are the 3 plasma proteins systems we discussed previously, they
are part of the other proteins in the inflammatory soup.
Albumin production decreases as liver spends its resources on acute inflammatory protein
production. Since albumin is a major blood plasma protein regulator of intravascular fluid
volume (BCOP) during capillary exchange, blood volume decreases as fluid that enters the
tissues is not pulled back in to the blood stream. This loss of blood volume causes the
hypotension.
Notice that an elevated body T (a fever) is indicative of a systemic response. Large increases in
WBC counts and the production of lots of plasma protein inflammatory and anti-inflammatory
mediators also indicate a systemic response. Measurement of body T, differential WBC counts
and inflammatory plasma protein markers are all used in diagnostics of disease.
Systemic Manifestations of Acute Inflammation
Fever
+ Elevation of core body temperature above the original hypothalamic set point of 37 C
✖ PYROGENS – fever inducing chemicals that can change the hypothalamic T set
point
✱ 2 types:


+ Endogenous pyrogens – body makes
+ Exogenous pyrogens – infections make infections agents make
+ Purpose of a fever?
✖ To inhibit bacterial growth
+ Complications of a fever?
✖ Tissue damage to cellular proteins (protein denaturation) ✖ Increase bacterial
endotoxin associated tissue damage ✖ Increased demand for O2 and glucose
✖ Dehydration, lethargy, malaise, hypotension
Body T is controlled in the hypothalamus of the brain, specifically in the
hypothalamic thermoregulatory center.
The hypothalamic thermoregulatory center senses changes in the temperature of blood and
CSF flowing in the hypothalamus.
2 types of pyrogens:
Endogenous pyrogens (EP) – cell-derived cytokines (IL-1 & TNFα) made by neutrophils and
macrophages after exposure to tissue damage or antigen- antibody (Ag-Ab) complexes; elicit a
fever response
Exogenous pyrogens – bacterial lipopolysaccharides (LPS), bacterial exotoxins, bacterial
endotoxins that are released as bacteria are destroyed, viral proteins, Ag-Ab complexes, some
drugs
Fever curve
This diagram illustrates the course of a fever beginning with (1) the release of pyrogens
(endogenous or exogenous). (2) Pyrogens trick the hypothalamus into thinking that the core
body temperature is too LOW; the hypothalamus responds by stimulating the physiological
mechanism that will (3) increase body temperature. Thus, the pyrogens trigger (4) the higher
body temperature that manifests as a fever. (5) Tx of the pyrogens means that either the WBCs
are busy phagocytizing those pyrogenic microbes or you take a fever reducing drug and there is
a ↓ pyrogens in your blood→(6) hypothalamus notices that you are too hot! and (7) starts the
physiological mechanisms that reset the hypothalamic thermostat back to normal (8). You
sweat.
Thus:


if ↑ pyrogens in your blood and/or CSF →hypothalamus thinks you’re cold! You
shiver and your body heats up.
if ↓ pyrogens in your blood and/or CSF →hypothalamus thinks you’re hot! You sweat
and your body cools down.
Fever also ↑ oxygen consumption by ‘hot’ tissues. This could be detrimental in a cardiac
patient whose body cannot tolerate the increased cardiac workload required.
Systemic Manifestations of Acute Inflammation (cont’d)
2) Leukocytosis
Dx by differential WBC count
Acute inflammation:



✖ ↑ number of circulating phagocytes – neutrophils, monocytes
✖ ↑ number of tissue phagocytes - macrophages and dendritic cells
✖ ↑ number of specific WBCs also determined by infective agent
Type of Infection WBC Inflammatory Effect
Bacterial
Neutrophilia
Parasitic
Eosinophilia
Viral
Lymphocytosis
Normal WBC counts are 5000-10,000 WBC per μL of blood
During a systemic inflammatory response to infection, a 2 – 3 fold increase in WBC counts may
occur. Since some WBCs such as eosinophils are quite rare, for a more accurate diagnosis, the
only way to detect a change in their number is to complete a more specific test called a
differential WBC count.
WBC differential – determines the % of each subtype of plasma WBC within the total plasma
WBC population.
Systemic Manifestations of Acute Inflammation (cont’d)
3) Increased acute phase plasma protein synthesis


+ Aka acute phase reactants or acute phase proteins of the 3 plasma protein
systems Part of fluid and/or cellular exudate
+ Part of the ‘inflammatory soup’
Many of the acute phase proteins are produced in the liver. Liver disease impairs the
inflammatory response making these individuals more prone to severe infections.
Possible Outcomes of Acute Inflammation
What are the possible consequences or outcomes of the acute inflammatory
response?
+ Inflammatory response successful! ☺
✖Wound healing occurs→ALL BETTER! or
+ Inflammatory response unsuccessful 
✖CHRONIC INFLAMMATION develops
We have now completed the acute inflammatory response!
Chronic inflammation occurs when the combined efforts of the vascular, cellular and plasma
protein responses have not successfully cleared the causative agent.
Think of some examples of chronic inflammation i.e. chronic diseases.
Chronic Inflammatory Response
Think of chronic inflammation as a
the host defenses and the causative agent
Think of chronic inflammation as a standoff between hostest defenses and the causative agents
Chronic Inflammation
✖Chronic Inflammation
+ Essentially an unsuccessful acute inflammatory response
+ Etiology:
✖ Continued presence of causative agent
✱ Infection: e.g. chronic tonsillitis, tuberculosis, HIV, hepatitis C
✱ Foreign body: e.g. shrapnel, asbestosis
✱ Foreign antigen: e.g. tissue/organ transplant rejection, hypersensitivity (allergy)
reactions
✱ Self antigen: autoimmune reactions e.g. RA, Type 1 DM, MS
✖ Repetitive (re)injury e.g. osteoarthritis, repetitive strain injuries,
carpal tunnel syndrome, workplace chemical exposures
+ Scar tissue produced
✖ Problem with scar tissue? Weaker than normal tissue; prone to reinjury
Chronic inflammation or the chronic inflammatory response develops when your vascular
(Lewis’s triple) response, your innate and adaptive immune cellular responses and all those 3
sets of plasma protein activations could not, collectively, destroy and remove the cause of the
tissue damage. Within a chronic inflammatory site there will be areas of new acute
inflammation as well as areas at various stages of wound healing.
Think back to the foundations and immune system review sections and the causes of increased
disease susceptibility and think of other causes from your own experiences, too.
Here are a few examples: age (very young and very old), immunocompromised, hypersensitive
immune reaction to repeat exposure, virulence of the infectious agent, strength and duration of
toxin exposure, repetitive reinjury.
Chronic Inflammatory Response
Fig. 6.11 in 1st Can. Ed. The chronic inflammatory response
Those poor neutrophils just can’t keep up! Chronically inflamed tissues are noted for the
presence of large numbers of macrophages and innate (dendritic/ NK cells) as well as adaptive
(B and/or T cell) lymphocytes and lots of fibroblasts.
Fibroblasts – secrete collagen – the barrier or wall; also responsible for scar tissue
formation
Macrophages – attempt to phagocytize and destroy causative agents; in this case they
are unsuccessful and overwhelmed by the damaging agent
Lymphocytes – primarily helper T cells – release lymphokines, immune signals that
activate macrophages and keep them in the site of chronic irritation
Look back at the slide of tonsillitis (purulent exudate) – remember that the bacteria have taken
up residence in the tonsillar macrophages waiting to develop an opportunistic infection when
the individual is immunocompromised for any reason, even a cold virus; the pustules consist of
dead and dying WBCs and tonsillar tissues and dead and dying bacteria.
✓Why is cellular exudate more prominent in a site of
chronic inflammation?
Pathogenisis of tissue damage from acute inflammation to
chronic inflammation or wound healing
This flow chart describes the pathogenesis of tissue injury as
it progresses to the acute inflammatory response followed
by either wound healing or chronic inflammation. Notice that
chronic inflammation can also progress to wound healing but
scar tissue formation is expected.
Lymphokines are chemical communication signals released
by lymphocytes. They are a subcategory of all those cytokines and chemokines that are part of
the inflammatory chemical mediators. Some lymphokines stimulate the adaptive immune
response, others keep the innate immune cells such as macrophages in the damage site.
Do you remember the two types of local lesions? Diffuse or focal? The way in which
macrophages function within a chronically inflamed site is called is called diffuse or focal
infiltration. If the macrophages keep wandering about through the inflamed tissue, that is
chronic non-specific inflammation. If the macrophages can’t destroy the causative agent, but
choose to to wall it off with the help of some fibrous collagen tissue, forming a granuloma, that
is called chronic granulomatous inflammation. Granulomas are a classic sign of tuberculosis
infection visible on a chest x-ray.
Two Patterns of Chronic Inflammation
Non-specific Chronic Inflammation
Chronic Granulomatous Inflammation
•Diffuse accumulation of macrophages and
lymphocytes
•E.g. Ulceration
•E.g. Rheumatoid or osteoarthritis
•Focal response that uses a fibrinous
(collagen) meshwork to ‘wall off’ the
infective organism→granuloma formation
•E.g. Tuberculosis lesions
Non-specific chronic inflammation – slide of G-I ulceration
Chronic granulomatous inflammation – slide of TB infected lung tissue
Look closely at all the tiny purple cells present in both histopathology slides. They are the huge
numbers of macrophages and lymphocytes that have infiltrated the damaged tissues and are
still trying to clear the damaging agent to allow wound healing to proceed.
TB – purple arrows indicate giant epithelioid Langerhans cells - phagocytic dendritic cells
located within a larger chronically inflamed fibrinous area called a granuloma. Granulomas are
typical of TB infection and containing viable tuberculin bacteria that are walled off by thick
collagen fibers. This type of lesion often develops a cottage cheese consistency called caseous
necrosis. Rupture of granulomas could allow release of these bacteria allowing them to spread
to nearby still healthy lung tissue or to be coughed out and spread by inhalation to other
individuals. More about TB in Respiratory Pathophysiology!
Lymphatic System Damage
✖Key Points:
+ Acquired etiology (most common)
+ Locally, lymphatic vessels and organs can also be damaged by direct
mechanical trauma
+ Since the lymphatic capillaries are ‘leaky’ so they can pick up excess tissue
fluid...lymphatic tissues are excellent conduits of transport and may become
inflamed due to:
✖ 1) local or systemic spread of infections; does the pt have a fever? or
✖ 2) blockage by neoplastic cells (metastasis) + Lymphedema may occur
Local: Chances are that if the tissue is bleeding, the small lymphatic vessels have also been
damaged. Part of the time it takes for the swelling to go down is the time it takes to heal the
lymphatic capillaries so they can start draining lymph away from the tissues.
Systemic: because lymph capillaries are more permeable than blood capillaries, they are often
conduits for the spread of infections or neoplastic cells. This is why a regional lymph node
biopsy is completed for a suspected cancer.
Lymphedema – excessive swelling of tissue due to blockage or loss of lymphatic flow
Clinical Manifestations of Lymphatic Tissue Inflammation
+ Lymphadenopathy
✖ Enlarged lymph node(s); palpable swelling of 1 or more lymph nodes with little or no
tenderness or pain
+ Lymphadenitis
✖ Painful, inflamed lymphadenopathy (i.e. enlarged lymph nodes); usually due to
infection
+ Lymphangitis
✖ Inflammation of the lymphatic vessels due to infectious or non-infectious causes;
follows direction of lymphatic drainage
Lymphadenopathy - palpable swelling of 1 or more lymph nodes with little or no tenderness
e.g. upper respiratory infection (URI) with enlarged cervical lymph nodes
e.g. lymphoma or Ca with metastatic lymph node involvement
Lymphadenitis – lymphadenopathy (i.e. enlarged lymph nodes) that is painful and shows signs
of inflammation (redness, tenderness); usually due to infection
e.g. tonsillitis is a common example of a local lymphadenitis
e.g. infectious mononucleosis (Epstein-Barr Virus; EBV) is an example of a generalized
lymphadenitis
Lymphangitis (lymphangitis) – inflammation of the lymphatic vessels due to infectious or noninfectious causes; follows direction of lymphatic drainage - watch for red streaks radiating _
(towards/away from) the heart.
Vaso- and angio- both mean vessel
Lymphadenopathy and Lymphadenitis
Tonsillitis – lymphadenitis due to viral or bacterial infections
Note pus formation in B and C. Pus formation indicates the presence of dead and dying
neutrophils and dead and dying bacteria. These are called purulent
or suppurative lesions.
Lymphangitis
An inflammation as a result of infection of the lymphatic
vessels; note red streak – which direction is the infection
travelling through the lymphatic system? Proximal or distal?
Hint- it is the same direction as venous return i.e. ____heart__ (towards/away from) the heart.
Inflammation and Wound Healing
1. State the 3 main purposes of the inflammatory response.



Limit further tissue damage by destroying, diluting the injurious agent
Protect against the spread of injurious agent by ‘walling off’ microbes/toxins
Begin the repair and regeneration processes – promote healing
2. Why is stromal tissue the major tissue involved in the inflammatory response?
Stromal tissue consists of vascular tissue and connective tissue
In wound healing – capillary buds respond to growth factors and initiate angiogenesis and
revascularization and fibroblasts (the major cell type in CT, respond to GF and initiate fibrosis.
3. Relate each of the 5 cardinal signs of inflammation to the vascular changes that occur during
acute tissue injury.
i. Redness (rubor) – arteriole and capillary vasodilation ii. Heat (calor) - arteriole and capillary
vasodilation
iii. Edema (swelling) (tumour or turgor) – increased venule (and some capillary) vascular permeability
iv. Pain (dolor) – edema and various acute phase proteins irritating nerve endings (e.g. prostaglandins
and kinins)
v. A 5th sign, loss of function (functio laesa) occurs if a joint is involved – due to edema and nerve ending
damage.
4. Explain the significance of axial and plasmatic zones in normal blood flow.
Axial zone – central area of blood flow within a vessel; where the blood cells normally travel; decreases
chance of contact of blood cells with endothelium lining the vessel and therefore decreases risk of
platelet-collagen interaction (if endothelial cells were damaged for some reason)decreased risk of
unwanted intravascular coagulation
Plasmatic zone – area right against the endothelial walls of the vessel; where blood plasma usually flows;
plasma has a bit of a lubricating effect to help promote smooth laminar blood flow
cause of edema
6. All fibrosis leads to scarring – true or false? Support your answer.
Fibrosis has 2 meanings in wound healing:
1) normal production of procollagencollagen as part of normal healing process – no
permanent scarring or functional deficits; and 2) excessive production of collagen that forms
scar tissue in a larger wound and may result in functional deficits. Therefore, fibrosis does not
always mean scarring and your answer is __false___?
Inflammatory chemical mediator
Complement proteins
Coagulation thrombin fibrin
Kinin proteins
Cell derived protein
Histamine – prostaglandins leukotrienes cytokines interleukins, interferon, tumor necrosis,
transforming growth factor TGFB
. Tissue mononuclear phagocytic cells (i.e. macrophages and dendritic cells) have many
different names, depending upon the tissue in which they were discovered. State the tissue in
which each phagocytic cell resides. FYI only but may help you in other readings.
Name of Mononuclear Phagocyte
Kupffer cell
Osteoclast
Langerhans cell
microglial cell
Histiocytes
Glomerular mesangial cells
Alveolar macrophages (dust cells)
Normal Tissue ‘ Residence’
liver
bone and periosteum
epidermal/dermal junction of skin
Cns
brain, breast, liver, lymph nodes, spleen,
tonsils, and placenta
Kidney
lungs
9. Complete the chart comparing primary, secondary and tertiary intention healing. Useto
indicate all that apply.
Description
Approximated edges
Wound contraction
occurs
Granulation tissue
forms
Scarring probable
High risk for infection
Acute inflammatory
response occurs
Eschar
Primary intention
yes
yes
Secondary intention
Tertiary intention
yes
yes
Yes
Yes
Yes
?
Yes
yes
Yes
Yes
Yes
yes
10. Wound healing is a good example of epigenetics in action. Explain this statement using the
physiological response of epithelial cells or fibroblasts during wound healing as your example.
Epigenetics refers to the altering of gene expression due to chemical modifications to DNA or
RNA. Altered gene expression as a result of tissue damage from any cause will allow epithelial
cells, fibroblasts and endothelial cells (really a subtype of epithelium) to produce proteins – actin
- that allow some level of cell motility (movement)
Endothelial cell contraction to allow for increased vascular permeability during the
inflammatory response
Epithelialization to cover the open surface of a wound to help prevent fluid and blood loss and
infection
Fibroblast infiltration of a wound site to produce a framework for wound repair and wound
contraction processes
Module 2 ends
Module 3 begins
Mechanisms of Defense and Repair
Wound Healing
Wound Healing: Purpose
✖Purpose of Wound Healing? + To restore normal tissue function
✖Healing begins during the acute inflammatory response (often within 24 hours) of
injury
✖Read the wound healing section of your textbook
Factors Influencing Wound Healing
Healing is Promoted by
Healing is Delayed by
Clean wound
Growth factors
Good nutritional status –
water, protein, vitamin C,
copper, zinc, selenium
Good apposition of wound
edges Good blood supply and
lymphatic drainage
Healthy immune system
Chronic inflammation: due to continued presence/repeat exposure to
causative agent or large area of necrotic tissue
Growth inhibitors
Poor nutritional status – dehydration, lack of nutrients
Poor apposition of wound edges
Poor blood supply and/or poor lymphatic drainage – elderly; CV,
respiratory or lymphatic disorders; tissue hypoxia Immunosuppression
(radiation, chemotherapy, immunosuppressive drugs (e.g. steroids,
NSAIDs); diabetes, elderly
Survival of stromal and
Loss of stromal and parenchymal cells – noticeable loss of function;
parenchymal cells for
scarring
regeneration - minimal loss of
function
Pathogenisis of tissue damage from acute inflammation to chronic inflammation or wound
healing
This flow chart describes the pathogenesis of tissue injury as it progresses through the acute
inflammatory response to either wound healing or chronic inflammation. Notice that chronic
inflammation can also progress to wound healing but scar tissue formation is expected. As you
know, scar tissue is weaker than normal tissue, so sites of chronic inflammation may show signs
of permanent deficits, even after they have healed.
We will now discuss the terms associated with wound healing that you see in this flow chart.
Wound Healing: Terminology
Terms Associated with Wound Healing
✖ Débridement
+ Clean the wound to remove causative agent
✖ Resolution
+ Injured cells recover; complete restoration to normal function, no deficits
✖ Regeneration
+ Replacement of dead cells by new cells of the same type (mitosis); no deficits
✖ Repair
+ Replacement of damaged tissue with fibrous scar tissue; deficits occur
Wound Healing: Débridement
✖Débridement (Fr. = to remove debris)
+ The process of cleaning up the wound site
✖ Includes removal of dead cells, necrotic tissue and foreign material
using physical, surgical or chemical means
+ Innate immune mechanisms involved?
➢Macrophages – clean up debris/microbes using phagocytosis
➢Flushing mechanisms – dilute and wash pathogen out/away; copious secretions
eg.?
➢Enzymes – proteolytic; disrupt pathogen biochemical structure
➢You?
➢Physical clean up using soap, water, forceps, alcohol, scrubbing...
❖If the wound is not cleaned of debris or is infected, it will not heal properly
→causes chronic inflammation, delayed healing and probable scarring
Remember the pathogenesis of chronic inflammation: persistent causative agent or repeat
injury/re-exposure. Patients really dislike physical débridement – it hurts, but it’s important!
Once the scrubbing is done, the tissue has been debrided.
• Proteolytic enzymes: destroy normal protein structure, including changing the 3D
morphological shape and/or removing amino acids. When the normal integrity of a protein is
changed, that protein cannot function properly e.g. bacterial or viral protein can’t make you
sick.
Wound Healing: Resolution
✖Resolution
+ Complete restoration of injured tissue to the original
structure and function
+ Damaged cells recover☺
+ Best outcome! ‘resolved’, no permanent deficits ❖May take as long as 2 years!
+ E.g. mild sunburn (no blisters!)
+ E.g. uterus post partum (post delivery)
Wound Healing: Regeneration
✖Regeneration
+ Production of new, healthy stromal and parenchymal body cells to replace those
damaged by the injury
+ Replacement occurs by mitotic cell division (mitosis)
+ Regenerative potential of tissues varies depending on specific cell type
✖ is that cell type capable of mitosis?
+ 3 Levels of Regenerative Potential:
✖ Labile cells
✖ Stable cells
✖ Permanent cells
Parenchymal cells are the functional cells of the organ. Their survival or ability to reproduce if
injured is vital to the ability of the injured tissue to return to normal function.
Refer to the chart on the next slide for details of specific cell regenerative potential. Be able to
define and give examples of each level of regenerative potential.
Regenerative Potential is based on the cell cycle and cell replication by mitosis. You may
remember the cell cycle from A and P. Here is a quick refresher:
Cell cycle


Events that occur during the lifetime of a cell
Includes interphase and mitosis (reproductive cell division) or meiosis (reductive cell
division) Mitosis

Mitotic cell division creates 2 new genetically identical daughter cells 2N = 46 →2
new somatic (body) cells each with full compliment of chromosomes
Prophase →metaphase →anaphase →telophase and then back to normal everyday
functioning in interphase Meiosis (FYI only here)

• Reductive cell division that separates pairs of homologous chromosomes so that each new
daughter cell contains one half of the original parent cell chromosome number 2N = 46 →N
=23 (haploid chromosome number in ova or sperm cells)
Regenerative Potential of Various Tissues
Tissue
Regenerative potential
Capable of mitosis; constantly
regenerating for normal tissue
Labile cells
maintenance and to repair small
wounds
Examples
Epithelium (e.g. epidermis, linings of digestive,
respiratory, urinary or reproductive tracts) Red
bone marrow – all blood cells
Endocrine and exocrine glands, liver
Do not normally divide but
(hepatocytes), kidney (glomeruli and nephron
Stable cells capable of mitosis if stimulated to tubules), smooth muscle, *fibroblasts,
do so by injury
osteoblasts, chondroblasts, vascular
endothelium, lung alveolar cells, neuroglia
None; cannot undergo mitosis
after very early childhood, even if
Permanent
Neurons, cardiac muscle, skeletal muscle (2+
tissue is injured and cells need
cells
years of age)
replacing; cells replaced by scar
tissue
I’ve made a few changes to this chart since the pre-recorded lecture. Use this version.
✓Which category of regenerative potential includes stromal cells?
__________________________________________
Endocrine glandular epithelium – produces hormones e.g. pituitary, pancreas, thyroid,
parathyroid, adrenals, ovaries, testes and the hormone producing cells of the hypothalamus
Exocrine glands include: sweat glands, sebaceous glands, ceruminous glands, mucous secreting
goblet cells, lacrimal glands and G-I secretions (saliva, gastric juice, intestinal juice, pancreatic
juice)
*Fibroblasts are usually considered stromal cells but are included to indicate their regenerative
potential. Tendons and ligaments are essentially pure collagen, so in those tissues, fibroblasts
are considered parenchymal.
Fibroblasts are also extremely hardy and survive most tissue injuries. Fibroblasts are
responsible for all collagen secretion including the subtype that creates scar tissue. Cancer
significance: labile cells with their high regenerative (mitotic) potential are the most likely types
to become neoplastic.
Wound Healing: Repair
✖Repair
+ Replacement of destroyed tissue with scar tissue + Scar tissue formation is called
fibrosis
✖ Made of a subtype of collagen that is produced by fibroblasts during prolonged
wound healing
+ Functions of scar tissue:
✖ Weaker ‘filler’ protein within a large wound or in an area of chronic
inflammation
✖ Replaces dead parenchymal cells but does not restore normal
tissue function →deficits occur
✖ Provides damaged tissue with up to ____ of original strength
Fibrosis is a term used to describe normal collagen production and scar tissue production.
Collagen is the major fiber type in all connective tissues (except blood).
Fibroblasts are the most common type of stromal cells; found in all types of connective tissues
(CT), except blood. They are very hardy, resilient cells that can survive in situations that kill
parenchymal cells e.g. severe hypoxia. During wound healing, fibroblasts will quickly ‘fill in’ the
wound site with secreted matrix, a combination of proteins and extracellular fluid. Whether or
not that matrix is a simply a framework for new parenchymal cells to repopulate the area or
remodels to become permanent scar tissue is dependent on the specifics of the situation (refer
to factors that promote and oppose wound healing for details).
Fibrosis: Collagen Production
✖Fibrosis
+ Production of collagen by CT cells called fibroblasts ✖ Confusing term with 2
meanings, depending on its location!
1) Fibrosis means normal collagen production during CT development, maintenance
and normal wound healing (i.e. healing without permanent scarring)
2) Fibrosis also means excessive collagen production that results in scar/fibrotic
tissue formation during wound repair
+ Collagen
✖ Collagen is a family of proteins of several
subtypes
✱ inloose(areolar)CT
✱ in tendons and ligaments
✱ in bone and cartilage
✱ in scars
✓Fibroblasts are _____ stromal/parenchymal cells
✓Fibroblasts are the hardiest cells in our bodies
The term fibrosis was initially used to describe the formation of protein fibers called collagen.
The term has since expanded to include normal basic CT maintenance and wound healing
production of collagen.
Fibroblasts can secrete several types of connective tissue protein fibers. In this section, we will
concentrate on collagen. Collagen is the most abundant CT fiber type.
Collagen production is regulated by gene expression within the fibroblasts. That gene
expression can change with circumstance. Collagen is therefore a family of proteins of several
subtypes that depend of the location and required function of the organ. Normal collagen in
healthy tissues and scar collagen are NOT the exact same proteins structurally or functionally.
Fibroblasts are extremely hardy cells that can survive injury that kills parenchymal cells – if
parenchymal cells are permanently lost, fibroblasts will ‘fill in the wound’ with scar tissue.
Functions of collagen in healthy CT development and maintenance and during wound healing:
• Normal collagen: long,strong,flexible protein fibers;provide tensile strength, flexibility and
protection to tissues; helps form a framework for parenchymal
cells as they reproduce to return damaged tissues to full function
Functions of collagen in scar tissue:

Scar tissue collagen: short, weaker, less flexible protein fibers; provide some
tensile strength to the healing tissue, but this collagen is weaker and less flexible than
normal collagen. It is essentially ‘filler’ to replace the lost parenchymal cells

Scar tissue will be weaker than healthy tissue; it can provide up to 80% of normal tissue
strength. The amount of scar tissue and its location will determine whether or not
normal or close to normal physiological activity is possible. Fibrotic (scar) tissue is not
the specialized tissue of the organ and cannot take over the job of the normal
parenchymal cells of the tissue.
Note: There is one more function of collagen to remember - when collagen comes in
contact with platelets, it triggers the coagulation cascade, so it is important to keep
collagen out of the blood stream to prevent intravascular thrombi!
Fibrosis – means production of collagen by fibroblasts. Fibrosis is normal in creation and
maintenance of healthy stromal tissues and is required in wound healing. Excessive fibrosis is
scar tissue formation.
A bit about dense regular and dense irregular connective tissues:

Dense CT collagen is arranged in regular rows, allowing strength and flexibility in
the direction of orientation of the fibers (e.g. normal tendon).

Dense irregular CT is arranged in a random pattern, allowing for some strength and
flexibility in all directions (e.g. pericardium, dermis and sclera.

Dense and irregular CTs are avascular tissues. In dense CT such as Achilles tendon
depicted above, the collagen is regularly arranged in long strong flexible bands with a
few fibroblasts that produced and secreted that collagen. This allows for strength of the
tendon along a specific direction, Injury happens when outside forces cause
overstretching of the collagen fibers and they break. In the tendon histology picture,
notice that all the pink collagen bands run in the same orientation - a regular pattern.





In scar tissue, the subtype of collagen that replaces the normal collagen is short, weak
and randomly arranged.
✓Can you see the differences in the healthy and the fibrotic tissue collagen in these
photos?
Normal collagen is a long, flexible, very strong fiber that provides ‘tensile strength’ to a
tissue.
• For example, the collagen in tendons and ligaments is a very long, strong, thick flexible
protein.
Scar collagen is very short, weaker and less flexible.
• Notice the random appearance of the scar tissue collagen
The Healing Process
• There are 3 overlapping steps/phases required for a wound to heal
1. Fill in the wound – with inflammatory exudate created during the
acute inflammatory response; débridement occurs; blood clot
formed (if necessary)
2. Seal the wound – via re-epithelialization at wound surface by
‘myo’epithelial cells
3. Shrink the wound – via wound contraction by ‘myo’fibroblasts
This is a new slide which I think explains the process and timing a little better. Please use it to
study from.
Wound Healing has 3 phases:
Phase I – Inflammation - begins immediately and lasts a few days, epithelialization
may continue into phase II, depending on the severity of damage
Phase II: Proliferation and Reconstruction – begins day 3 – 4, lasts about 2 weeks Phase III:
Remodeling and Maturation – from several weeks to up to 2 years
Note the overlap in phase I and II and again in phase II and III – the exact length of each phase
depends on the severity and location of the wound. Good blood flow and lymphatic drainage
are required; if compromised, healing will take longer. The length of time required for a tissue
to complete phase III is also dependent on the specific tissue type, including the regenerative
potential of each cell type that is injured.
Two Major Cell Types Involved in Wound Healing
Two Major Cell Types are involved in Wound Healing
1. Macrophages
✖ Major phagocytic ‘clean up’ cells


+ Early: Cellular débridement
+ Promote wound healing by secreting
chemical mediators
• E.g. angiogenic factors and fibroblast growth factors

+ Later: Blood clot dissolution
2. ‘Myo’fibroblasts
✱ Early: Move into the damage site and secrete collagen fibers – form
framework/scaffolding for parenchymal cells to re-establish in the site
✱ Later:Wound contraction to shrink size of wound
Macrophages involved in wound healing tend to be the newly arrived M2 subtype, although
some of the original tissue residing macrophages (M1) may still be alive and helping with the
wound healing.
Angiogenic factors are chemicals that stimulate the production of new arterioles, capillaries,
venules and lymphatic capillaries during wound healing. You will hear more about these factors
in the cancer biology and cardiovascular modules.
Fibroblast growth factors stimulate the mitotic division of fibroblasts within the wound site.
What are (myo)fibroblasts?
✓Do you remember the (myo)endothelial cells that could contract to make venules more
permeable during the vascular response?
(Myo)fibroblasts are fibroblasts in which the gene to make the protein actin has also been
turned on. They are called myofibroblasts due to their ability to migrate into the wound site.
Just like with the endothelial cells, myofibroblasts can ‘contract’ around the edges of a wound,
helping to decrease the overall size of the wound. That pulling sensation you feel as a wound
heals tells you that myofibroblasts are at work causing wound contraction, a normal part of
wound healing. The process can also jangle local nerve endings producing an itchy feeling.
Following wound healing, actin secretion ends and the cells return to being normal tissue
fibroblasts. Collagen acts as a scaffolding or framework within the fragile healing wound.
Parenchymal cells will repopulate the wound using the collagen as a protective framework.
Preview! – just wait – during wound healing, those parenchymal cells that are able to
regenerate, especially epithelial cells, can secrete actin, too! What would these epithelial cells
be called? _________myofibroblast______________________. They will migrate into the area
of the new collagen framework of the damaged tissues and take up residence there.
Blood clot dissolution – i.e. the destruction of the blood clot, begins once the endothelial lining
of the vessel has healed. A liver derived protein called plasmin is used to enzymatically digest
the fibrin threads (a process called fibrinolysis). Macrophages will phagocytize any
degenerating RBCs or platelets that are trapped in the tissue space (i.e. part of any bruising of
the injured tissue).
Types of Wound Healing
✖3 Types of Wound Healing
1. Primary (first) intention healing
2. Secondary (second) intention healing
3. Tertiary (third) intention healing
✖ Factors that determine specific type of healing



+ Severity of tissue damage
+ Presence of risk factors/causative agents that delay or complicate the healing
process
+ Increased severity or complications such as comorbidities will increase the
probability of scar tissue formation
Comorbidities:

Individual has more than one risk factor or already has a specific disorder that
places the individual at higher risk for serious illness

E.g. why we are currently in social isolation, practicing social distancing in order to
keep our older population, those with pre-existing respiratory illness or individuals who
are immunocompromised safe from infection by covid-19
Comparison of Primary and Secondary Intention Wound Healing
Primary Intention Healing
 ✖ Healing of a wound with
minimal tissue loss, no infection
 ✖ Clean wound with good
apposition of wound edges
 ✖ Minimal parenchymal and
stromal loss →resolution and/or
regeneration possible
 ✖ Original tissues structure and
function restored
 ✖ Minimal, if any visible scarring
 ✖ Minimal, if any loss of normal
function
 ✖ E.g. Surgical incision, minor
cuts that heal quickly
Secondary Intention Healing
✖ Healing of a large wound (open
wound), high risk for infection
✖ Extensive débridement required;
wound edges are separated
✖ Wounds have significantly more
parenchymal and stromal tissue loss
→resolution and regeneration difficult;
requires repair processes
✖ Noticeable scar formation
✖ Weakness and/or loss of normal
tissue function may occur
✖ E.g. lacerations, burns, ulcers
The method in which a wound heals can be classified as primary, secondary or tertiary wound
healing.
In Pathophysiology 1 we will discuss primary and secondary wound healing in detail. Tertiary
wound healing is a complicated form of purposely delayed wound healing is briefly defined
here but discussed in detail in future courses.
Apposition of wound edges – do the two sides of the wound align/meet? Good apposition
improves wound healing – this is why bones need to be set in alignment and then casted to
prevent the bones from moving while they heal.
Tertiary (Third) Intention Healing 3rd intention of healing


✖ Aka delayed healing, delayed primary intention or delayed closure
✖ Healing of a complicated wound that is purposely left open (usually for 3 –
5 days)
+ Why? Infected wound needs lots of debriding, presence of necrotic tissue, crush
injuries, poor vascularization, drainage required



✖ Once healthy granulation tissue is present and wound is clean of debris and
infection, wound edges are approximated and wound is closed with sutures or
staples or a skin graft
✖ Scarring probable
✖ Discussed in detail in future courses such as wound care
+ Don’t choose it as an answer in ZOOL 1073!
Examples of tertiary intention healing include:
E.g. Surgical incision left open for drainage - due to edema and/or infection E.g. Slow wound
healing due to poor blood flow e.g. decubitus ulcer, diabetic ulcer
E.g. Severe crush injuries with extensive vascular damage - presence of necrotic (dead) tissue
E.g. Severely infected wounds requiring extensive debridement over several days/weeks
Examples of Tertiary Wound Healing
First picture: Note presence of necrotic tissue.
Eschar (pronounced es kar)
– area of necrotic tissue on the skin surface; also called slough
– forms a hard crust or scab of black tissue common in diabetic ulcers and burns – is a normal
part of the wound healing process
Eschars and slough (usually pronounced sloff in Canada) Second picture: before and after
surgical skin grafts.
3 Phases of Wound Healing three phases of wound healing
1. Phase I: Inflammation
▪Starts immediately; days 1 – 3
▪Initial tissue injury; followed by acute inflammatory response
Phase II: Proliferative and Reconstructive (new tissue formation) Phase
Days 3 or 4 to ~ day 14
Involves: WBC infiltration and phagocytosis,
formation, angiogenesis and re-epithelialization occur, fibrosis and wound
contraction begin
Phase III: Remodeling and Maturation Phase

▪ ~ day 14... 2 years





▪ Involves: resolution, regeneration and/or repair of parenchymal and
stromal tissues – fibrosis and wound contraction completed
Why the large time frame range in phases II and II?
You already know quite a bit about steps 1 and 3! We will review them a bit but spend
most of our time on step 2.
Key concepts:
Look for the new terminology to define and watch for the time frame of each of the 3
steps.
We will discuss normal wound healing using the 1
are different in the other texts. If you are using a different text, I suggest you use the
one’s in these slides to study. They are a simpler format.
Wound Healing: Phase I
Phase I: Inflammation – the acute inflammatory response
Immediately following tissue injury


Acute inflammatory response begins as tissue mast cells secrete histamine
→transudate presents →wheal and flare reaction
Hemostasis and thrombosis occur, prn
• If thrombus is present, helps to fill in the wound
Within a few hours




5 inflammatory signs present
Fluid exudate presents
Neutrophils and a few macrophages infiltrate wound site →cellular exudate
presents →fill in the wound
Cellular débridement begins→phagocytosis of cell debris and microbes
❖This is the best time to debride the wound!
As you read through these slides re: steps involved in the healing process, refer to Fig 6.13 in
your text (either edition)
Note: Primary intention healing – Fig. 7.19 A – D
Secondary intention healing – Fig. 7.19 E – I
PMNs = neutrophils the ‘scouts’ of the innate immune cells; can detect very small levels of
chemotactic distress signals; phagocytic first responders.
Steps involved in the Healing Process
Phase I: Injury and Acute Inflammatory Response
Begins immediately -Histamine release stimulates the vascular response: Lewis’s triple
response→transudate produced→5 signs of acute inflammation begin
Hemostasis initiated: vascular spasm, platelet plug formation→blood clotting cascade →blood
clot forms and helps to fill in the wound
• Note: thrombosis is the formation of a blood clot
Within 2 – 3 hours
Cellular and plasma protein responses fully developed, acute inflammatory exudate present
(fluid and then cellular exudates present); exudate helps fill in the wound site


Notice that within 2 – 3 hours all aspects of the acute inflammatory response – vascular,
cellular and plasma protein responses are occurring to try to prevent further tissue
damage.
Physical débridement, if required, should occur during this phase of wound healing.
Wound Healing Phase 2
Wound healing phase two
Phase II: Proliferation and
Reconstruction
Begins within 3 – 4 days→up to 2
weeks



✖ Wound begins to heal
✖ Macrophages complete cellular
débridement, secrete
biochemical mediators to
promote healing and
begin clot dissolution
✖ ‘Myo’fibroblasts
infiltrate wound - fibrosis
creates collagen framework that helps parenchymal cells ‘find their way’ to
wound site
✖ Granulation tissue formation - creation of new vascular healing tissue
✱ Includes angiogenesis – creation of new blood and lymphatic
microvessels →revascularization of damaged tissue
✖ Re-epithelialization begins - ‘myo’epithelial cells proliferate →migrate from
wound edges to cover wound surface →begin to seal the wound
✖ Parenchymal cell differentiation begins – local ‘myo’parenchymal cells infiltrate
wound →begin resolution or regeneration (if possible)
✖ Wound contraction begins – ‘myo’fibroblasts at wound edges ‘contract’ to begin
to shrink wound size →decrease size of potential scar
Be able to define all of the highlighted terms re: steps involved in wound healing
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Cellular level debridement completed, macrophages secrete many biochemical
mediators that promote healing: transforming growth factor beta (TGF-β) signals
fibroblast infiltration, angiogenic factors stimulate revascularization and matrix
metalloproteinases that help with constant remodeling of the wound site as the healing
progresses. During organization, histamine levels return to normal, 5 inflammatory signs
diminish
Clot dissolution means the destruction of the blood clot. This requires the enzyme,
plasmin. Plasmin is made in the liver and circulates in the blood plasma as the inactive
precursor plasminogen. Activated plasmin dissolves the fibrin threads – a process called
fibrinolysis. The clot needs to be removed so that new parenchymal and stromal cells
can enter the area. If the tissue is still bleeding, then reconstructive phase will be
delayed.
Healing begins when granulation tissue starts to grow into the wound site from the
surrounding healthy tissue. Granulation tissue is healing tissue, including new blood and
lymphatic capillaries (angiogenesis), fibroblasts and the collagen they make.
‘Myo’epithelial cells along the wound edges begin the process of epithelialization.
During epithelialization, healthy epithelial cells along the wound edges undergo mitosis
(labile cells) and begin to migrate horizontally onto the denuded tissue surface. When
cells from opposite sides meet, they secrete basement membrane, anchor and begin to
divide in a vertical plane to seal the wound. Once wound is closed, contact inhibition
between adjacent epithelial cells stops further mitosis that could cause production of
excess epithelial cells. During this phase, parenchymal cells of the specific tissue will also
recover (resolution) or regenerate, if possible. Parenchymal cells use the collagen
framework as a guide to where they should be. Guess how they move into the area?
‘myo’parenchymal movement!
Fibrosis, angiogenesis and epithelialization are carefully regulated by a variety of
growth factors made by fibroblasts and macrophages
collagen production factors e.g. transforming growth factor β (TGF-β) and
fibroblast growth factor (FGF)
 angiogenesis factors e.g. vascular endothelial growth factor (VEGF), fibroblast
growth factor (FGF)
 ECM (extracellular matrix) and collagen remodeling factors e.g. matrix
metalloproteinases (MMPs)
Fibroblasts are integral to wound healing. Healthy fibroblasts need vitamin C (think of
the C for collagen synthesis) and O2
Note: abnormal gene expression of wound healing growth factors has been implicated
in cancer pathogenesis
How many different types of cells were capable of turning on the actin gene and
undergoing some form of ‘myo-contraction’?
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✓List them here!
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Fig. 6.13 Wound Healing by Primary or Secondary Intention
Primary intention: wound edges are in close apposition – it’s a small wound, no
infection or other foreign material trapped in it. E.g. clean surgical incision Secondary
intention: bigger wound so harder to achieve good apposition of wound edges
If you have an alternate textbook, you can use the figure in this slide or those in your
textbook. I find the figure in this slide a bit simpler to follow. If you are using the 7th or
8th Ed., see below:
Primary intention healing
A and B - Phase I
C and D - Phase II and III – In C, a collagen framework is created to allow tiny blood and
lymphatic vessels and parenchymal cells to find their way into the wound site. Epithelial
cells at the surface are also dividing to replace those lost (re- epithelialization);
fibroblasts will ‘contract’ to pull on the wound edges. Re- epithelialization and wound
contraction both help to seal the wound from pathogens and decrease the overall size

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of the wound to limit scarring.
Secondary intention healing
Fig. 7.19 E and F - Phase 1
GandH- Phase2
I -Phase3
Note: primary intention healing is also called first intention healing
secondary intention healing is also called second intention healing tertiary intention
healing is also called third intention healing
Visualizing Granulation Tissue
Histological (microscopic) view – black arrows indicate islands of bright pink, vascular
granulation tissue; lighter pink is collagen and dark purple nuclei represent fibroblasts Gross
morphology (visible with your naked eyeballs) – this is a skin wound
1= pus (which needs to be removed for healing to be successful, a process
called____________________?
2 = granulation tissue
Granulation tissue is healing tissue composed of ‘myo’fibroblasts that migrate from the edges
of the wound site and newly formed capillary buds and loops. Revascularization of the injured
tissue is called angiogenesis. Lymphatic buds form a few days later; once they become new
lymph capillaries excess tissue fluid can be drained and edema will lessen.
Granulation tissue is pink and granular in appearance. The new capillaries are fragile and very
leaky, so edema will still be present in the injury site. Revascularization is imperative for wound
healing to progress. The fibroblasts in granulation tissue are sometimes called myofibroblasts
due to their ability to migrate into the wound site. (Myo)fibroblasts are responsible for fibrosis.
They secrete extracellular matrix (ECM) including the protein procollagen, a precursor to
mature stronger collagen fibers during the next several weeks or months of wound healing.
Newly formed collagen is very weak but does provide a framework for both revascularization
and epithelialization to proceed.
Fibrosis has 2 meanings in wound healing: 1) normal production of procollagen →collagen as
part of normal healing process; and 2) excessive production of collagen that forms scar tissue in
a larger wound.
Wound Healing: Phase II (cont’d)
Phase II: Proliferation and Reconstruction (cont’d):
Within 14 days
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+ Re-epithelialization complete →seal the wound
+ Parenchymal cells begin re-establishing function (if possible)→fill in the
wound
+ Scab forms
✖ Dried epithelial cells and dried blood clot - loosens and falls off
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+ Clot dissolution completed by enzymatic digestion by plasmin
+ Wound contraction may be complete
✖ ‘Myo’fibroblasts continue to ‘contract’ to shrink wound size →may stimulate some
prostaglandins →might be itchy
Wound contraction is most noticeable in a larger wound such as a surface abrasion, where it
helps to decrease dehydration and infection; not so necessary in a paper cut. A wound is often
itchy during wound contraction due to release of prostaglandins that irritate local nerve
endings.
Clot dissolution should not begin until re-epithelialization is complete!
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The removal of the blood clot should not occur until epithelialization is complete,
otherwise, the wound site will bleed again.
Macrophages will phagocytize some clot components e.g. old platelets and RBCs
Plasminogen converts to plasmin – plasma protein that circulates as inactive
plasminogen; active enzyme called plasmin. Plasmin dissolves fibrin threads in a process
called fibrinolysis. Any still healthy trapped platelets or RBCs will return to normal
circulation; dead cells will be recycled in the liver or spleen
9.
What is a scab? Name the constituent parts _Dried epithelial cells and dried blood clot
Wound Healing Phase 3 wound healing phase three
Phase III: Maturation Phase (aka remodeling)
From 2+ weeks to months to years
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+ Wound healing continues, stromal/collagen remodeling continues;
parenchymal function returns (if possible)
+ Resolution: ☺return to original tissue integrity: no scarring, no deficits
+ Regeneration: ☺degree of scarring and deficits determined by regenerative
potential of organ’s parenchymal cells

Labile and stable cells: minimal, if any scarring or deficits
 Permanent cells: die, scar tissue replaces them If CNS damage,
CSF fills the space
+ Repair: tissue damage severe with loss of parenchymal cells; scarring and
possible deficits present
The type of wound healing that occurs depends on the severity of the injury and whether or not
the wound is clean or infected. Any factor that inhibits wound healing will allow for the
deposition of more scar tissue collagen. Minimal or no replacement of dead parenchymal cells
will cause remodeling phase to include scar tissue formation.
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Time frame determined by overall severity of tissue damage
Stromal cells and collagen framework undergo remodeling and re-arrangement along
normal stress lines of the tissue, trying to re-establish tissue integrity and strength
Time Course of Cells Infiltrating a Wound
Think about the timing of each cell infiltrating the wound site and relate that time frame to the
function of each cell type during inflammation and wound healing.
✓Relate the time course of cell infiltration to the role of that cell type in wound healing. I
have listed them below in the order in which they appear.
Platelets:
Neutrophils:
Macrophages:
Fibroblasts:
Lymphocytes:
This figure illustrates the steps in wound healing in days...years in relation to the relative return
to strength of the wounded region.
2 Minute Review: Wound Healing
2 Minute Review: Wound Healing
1. During wound healing, neutrophils are prominent in phase 1
whereas macrophages are prominent in phase 2
2. Collagen is made by CT stromal cells
(choose one), specifically called fibroblasts.
3. The ability of a damaged tissue to return to normal physiological activity depends
on the relative balance between parenchymal cell and stromal fibroblast cell
activity.
4. What is fibrosis? Production of collagen
5. Is fibrosis normal or abnormal? both
6. Does all fibrosis cause permanent scarring? no
7. Where does scar tissue form? In the stroma
8. Why is granulation tissue pink? Healing, highly vascular tissue
Now for 2 slides of wound healing review questions! These ae new questions that are not in the
pre-recorded lectures. Don’t worry, the answers are here, too.
Think about these questions and be sure to use the key pathophysiology terms in your answers.
2 More Minutes Review: Wound Healing
9. What is a scab? Dried epithelial cells and dried blood clot
10. What do you see if you ‘pick’ a scab? Granulation tissue
11. What determines the extent of scar tissue formation within a wound? The amount
of collagen deposited in the wound site
12. Why are scars white? Collagen is avascular
13. Why does picking that scab increase your risk of scarring? Promotes fibroblast
production of excess collagen
14. Why does a healing wound itch? Wound contraction elicits prostaglandin (PG)
secretion; PGs can stimulate pain receptors
15. Repair by scar tissue formation can provide up to 80 % normal tissue strength.
16. How long does it take to completely heal that sunburn you got last July?
Approximately 2 years!
Dysfunctional Wound Healing
Self-study Testable
Types of Dysfunctional Wound Healing
1. Contractures
2. Adhesions
3.
4.
5.
6.
Keloids
Hypertrophic scars
Dehiscence
Proud Flesh
This section is self-study but testable material.
Be able to define these terms related to dysfunctional wound healing. Dysfunctional wound
healing means that normal tissue function is not restored, hence notice that presence of scar
tissue is a common factor.
Dysfunctional Wound Healing Contractures
Contractures
+ Thick scar tissue and excessive wound contraction
+ Severely impedes normal function
+ Possible disfigurement e.g. severe burns; prolonged
hypertonic spasticity
Photo is of Dupuytren’s contracture
Dysfunctional Wound Healing: Adhesions
Fibrinous exudate in peritonitis
Adhesions
✖ Secretion of excessive fibrinous (fibrin containing) exudate
✖ Causes serous membranes to adhere to each other restricting organ movement
+ Serous membranes
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✖ Pleural membranes
✖ Pericardial membranes

✖ Peritoneal membranes
Serous membranes surround the thoracic and abdominopelvic body cavities. They secrete a
clear watery lubricating fluid that allows the organs they enclose to move freely (without
friction).
Pleural membranes surround the lungs; inflammation called pleurisy
Pericardial membranes surround the heart; inflammation is called pericarditis Peritoneal
membranes surround abdominal and pelvic organs; inflammation is called peritonitis
Dysfunctional Wound Healing: Keloids and Hypertrophic Scars
Keloids and Hypertrophic Scars are due to overproduction of collagen
✖ Keloid scars overgrow the size of the wound; do not decrease over
time
✖ Hypertrophic scars are raised but remain within the wound
boundary; may reduce in size over time
Keloids are most common in those with darker skin tones.
Risk factors include: familial predisposition to both scar types and location of the lesion
Common locations? Neck, thorax, shoulders, upper arms
Dysfunctional Wound Healing: Dehiscence
Dehiscence
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✖ Breaking open of a poorly healed sutured
wound
✖ Most common in the abdomen due to
high intra-abdominal pressure
✖ Other causes:
o + Infected site, presence of foreign
object, obesity, steroid use
o + Co-morbidities e.g. diabetes, renal
or liver disease, presence of
neoplastic tissue
Notice the suture lines on this abdominal wound. Scarring will occur with healing of this
wound.
Proud Flesh
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✖ Overproduction of pink granulation tissue that protrudes out of
the wound
✖ Causes:
+ Poor healing due to persistent infection or foreign object
Veterinary note: proud flesh is often a problem in horses and cattle, especially
on their legs.
Review Question 1
A large open wound that has formed scar tissue as it healed is an example of which
type of healing?
1. Primary
2. Secondary
3. Tertiary
4. Débridement
5. Regeneration
ANSWER AND RATIONALE: 2. Secondary. Secondary intention healing occurs when scar tissue is
formed and a large area of tissue is destroyed. With an open wound, epithelialization, scar
formation, and wound contraction take longer and healing occurs through secondary intention.
1. Primary healing occurs when there is minimal tissue loss. Wounds that heal under conditions
of minimal tissue loss are said to heal by primary intention.
3. Tertiary healing is a delayed form of healing where the wound site is specifically
left open because of infection, necrotic tissue, loss of vascularization or to drain excess
tissue edema (e.g. within a body cavity). These wounds are then surgically approximated
to pull the wound edges and the healing granulation tissue into good alignment for
healing. Scarring often occurs.
4. Débridement is the removal of dead tissue cells, microorganisms, and dissolved clots by
cellular or physical means.
5. Regeneration is the returning of injured tissue to its normal structure and function with
no scar tissue. An open wound would have scar tissue.
Module 2 ends
Module 3 beings
Definition of Stress
Stress is commonly defined as a state of real or perceived threat to homeostasis.
Homeostasis
What is Homeostasis?
+ Relatively constant internal balance/environment; defined ‘set points’ that keep cells in
a normative state by providing:
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optimal concentration of gases, nutrients, ions and water
optimal temperature for metabolism
optimal intracellular and extracellular (tissue) fluid volumes
Maintained by feedback control mechanisms that are designed to prevent significant
changes from the set point
• Why? To protect normal cellular structure (morphology) and function in order to
maintain health of all body systems
Homeostatic Control Systems
✖Homeostasis relies on negative feedback mechanisms
✖Which 2 body systems control homeostasis? Nervous and endocrine system
Stress affects Homeostasis
Stressor
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Any external or internal stimulus (variable) that causes a change in the
internal homeostatic balance (i.e. creates detectable homeostatic imbalance)
2 Types of Stressors
Distress = bad stress; negative
o Etiologies with potential for tissue damage
o Genetic, congenital or acquired causes
o Chemical, physical and psychological agents
o Eustress = good stress; positive
o Energizes, motivates
o e.g. laughing, exercising, sleeping
Homeostasis is dynamic; subtle changes such as an increase in heart rate when you get up from
the computer and walk to the kitchen to make a cup of tea are normal and the body systems
quickly respond to the change, returning the heart rate to resting state when you sit down
again.
As we work through this module, keep in mind that stress is a normal event and the stress
response is designed to alert the body to potential issues, respond to those issues and then
return to normal homeostatic balance.
Different individuals will be affected by and respond to the same type of stressor to different
degrees. This is why stress can manifest in many different psychological
(behavioural/emotional) or physiological ways. It is also why the mechanisms used to overcome
the stressor, or adapt to it if necessary, are also different in different individuals. Some authors
suggest that previous life experience of negative and positive stressors help to condition the
individual to new stressors, enabling the individual to cope more efficiently.
Category of stressors
Category of Stressor
affecting Homeostasis
Examples of Internal
(Endogenous) Stressors
examples of External
(Exogenous) Stressors
Chemical Stressors
BG, blood gases, F&E (water/
ions/pH), NT, hormones,
blood cell counts, Hgb,
nutrients, microbes
(infection), drugs,
inflammation, antibodies
Low O2 or high CO2 levels in
air, pollutants, microbes
Physical Stressors
BP, CO, BV, urine volume,
ventilation, body T,
mechanical trauma
(compression, obstruction,
fracture), excess weight gain
or loss, mobility issues, age
Barometric (air) pressure, air
T, mechanical trauma (e.g.
MVA or sports injury), excess
noise or light levels, work
hazards
Psychological (Emotional)
Stressors
Pain, fear, anxiety, loneliness
Relationships: family, friends,
work, school, social media
This is a short list of possible internal and external environmental stressors – i.e. variables
within the body that can alter homeostatic balance. A change from the normal set point of any
of these variables would be detected by different body receptors and sent to a control center
(normally in the CNS and often the hypothalamus). The control center would then send signals
via effectors to respond to this change and return the variable towards the normal,
homeostatic state. This is the definition of a negative feedback system.
Notice that an abnormal balance in any of these variables could result in disease or illness! Feel
free to add other variables to the lists.
Many chemical, physical and psychological factors can affect homeostasis, thus they must be
constantly monitored to maintain cellular and emotional health. Your body cells live within the
internal environment. The external environment is where you live and interact with others.
Changes in internal or external environmental variables can trigger a stress response. If the
change becomes permanent, the body cells will try to adapt. Chemical and physical changes are
often measurable and used in diagnostics. Psychological changes are equally important, and
may include behavioural changes. Regardless of the type of stressor, the body will try to
respond to the homeostatic imbalance by returning the body to a state of ‘normalcy’ using a
negative feedback system. But what if the stressor is long term i.e. chronic? Then the body will
attempt to adapt to the change. Allostasis is the process of that adaptation to change. If the
body cannot adapt, manifestations of chronic stress-related disorders may occur.
Homeostatic Imbalance
✖ Homeostatic Imbalance
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
+ Occurs when normal homeostatic mechanisms are unable to return a
physiological process to normal status (i.e. the normal physiological set point)
+ Negative feedback control mechanisms will try to re-establish homeostatic
✖ If moderate imbalance?

+ May result in physiologic or psychological adaptive
changes to the normal set point; called allostasis

+ Clinical manifestations subtle/subacute or not
observed; may be physiologic and/or behavioral
✖ If severe and/or chronic imbalance?

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+ Body not able to adapt to stress: body enters allostatic overload
+ Clinical manifestations present
+ Stress-related illness, disease, death


How to imagine homeostatic imbalance?
Common analogies for homeostatic imbalance are a teeter totter or a pendulum.
The teeter totter is stuck in one position; not adjusting back to the normal, homeostatic
set point. Or the pendulum swings too far in one direction.
Allostasis
✖What is Allostasis?
+ The adaptation(s) that occur in response to a chronic change in the homeostatic set
point of a variable
✖ Often described as stability through change – a ‘new normal’ meant to prepare
for future stressors
+ Allostatic adaptations may include:
✖ Structural cellular adaptations, and/or
✖ Physiological cellular adaptations, and/or
✖ Psychological/behavioral adaptations
+ Individualized response to stressful event determined by conditioning factors
✖ Internal conditioning factors
✖ External conditioning factors
+ Adaptations are mediated by changes in neuroendocrine, autonomic and immune
functions
Allostasis: the process of cellular adaptation to a constant/chronic change in homeostatic
balance, a new set point is established. This new set point involves physiological changes in the
neuroendocrine, autonomic and immune system functions resultant from the chronic stressor.
Allostasis is integral for cell survival to chronic homeostatic imbalance.
Adaptation: the structural, physiological and psychological processes utilized by the individual
(or individual cells) to respond to a stressor. Recall the different cellular adaptations discussed
in altered cells. These structural and functional alterations are adaptations to chronic change;
allostatic changes have occurred. These changes may be used diagnostically and prognostically.
How the body adapts to long term stress is extremely variable. The same individual may
respond to a stressful event differently at different times.
This is thought to be due to internal or external conditioning factors.
Internal conditioning factors include genetic predisposition, age and gender.
External conditioning factors include exposure to environmental agents, life experience,
dietary factors and/or socioeconomic factors.
Allostasis is Adaptation to Continued Homeostatic Imbalance
✖Why is allostasis important?
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
+ Body is trying to structurally, physiologically and/or psychologically survive the
changes resulting from the chronic homeostatic imbalance
+ What are some examples of
allostatic adaptations?
✖ Structural adaptations
✖ Physiological adaptations
✖ Psychological/behavioral
adaptations
Physiological and behavioral stress
responses. The body can adapt to stress,
at least to a point. Notice that an
individual’s physiological responses to
stress are determined by a number of modifiable and non-modifiable risk factors. These risk
factors are the allostatic load that stimulates physiologic and/or psychologic responses.
A person’s ability to adapt to stress is individualized. Psychological stressors may elicit a
physiological stress response and vice versa. Your text describes these psychological stressors
as anticipatory responses or reactive responses.
Be able to define these terms:
Allostasis
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
Dynamic, adaptive physiologic and behavioral responses to stressors that can
potentially change the homeostatic set point to a new ‘normal’ range.
Short term adaptations to a stressor that do not return to original set point; become the
new, continuous norm for a particular set point.
Allostatic load
• Individualized cumulative amounts of stressors that exist in our lives and affect our
physiologic responses (genetics, lifestyle, daily or sudden events).
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The physiological and behavioral manifestations of these stressors are determined by
our ability to adapt to the stress load, including various coping mechanisms.
Includes the beginning of physiologic adaptive changes in neuroendocrine, autonomic
and immune systems that occur in response to continued stressors.
 Neuroendocrine/autonomic: chronic activation of sympathetic NS→resistance
stage of GAS, especially secretion of cortisol
 Endocrine: increased cortisol and other hormones plus activation of the reninangiotensin-aldosterone system (RAAS)
 Immune: immunosuppression
May have subtle clinical manifestations or none at all.
Allostatic overload

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The body is having difficulty managing the cumulative stressors and begins to manifest
the effects of a loss of its reserves and its ability to continue to respond to and survive
the stress.
Body may transition from resistance to exhaustion stage of GAS (our next topic).
Clinical manifestations should be present.
May lead to long term deficits, including stress-related diseases.
E.g. chronic stress causes a prolonged increase in cortisol that the body must adapt to
by subtly changing its physiology – minimal, if any manifestations may be present for a
long time (this is allostatic load), but, eventually, this increased cortisol manifests as
increased BG, HR, BP and decreased immune function...and may lead to allostatic
overload which could manifest as stress-related disease(s).
Neuroendocrine Regulation of the Stress Response
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The nervous system and endocrine system both respond to stressors. This
neuroendocrine response to stress is normal and allows the body to react to and survive
acute stressors such as tissue damage. In a normal stress response, the
neurotransmitters and hormones released are quickly removed once the stressor is
alleviated. This is a normal neuroendocrine negative feedback response to a return to
homeostasis.
The neuroendocrine response (via neurotransmitters and hormones) to a stressful event
can affect the function of the immune system and immune functional changes can affect
the neuroendocrine system.
We will review the normal neuroendocrine and immune stress responses and then
consider allostatic adaptations that occur as the body is trying to survive chronic

changes to these neuroendocrine and immune mediators due to the presence of
chronic stressors.
As you read this section, begin to make a mental list of some chronic stress-related
disorders.
Hypothalamus Regulates the Neuroendocrine Stress Response
The neuroendocrine stress response consists of cognitive, behavioural and physiological
responses designed to restore the body to homeostasis. The hypothalamus controls the body’s
physiological responses to stress.
The hypothalamus is both a neural and an endocrine organ. Neurologically, the hypothalamus
is the major regulator of the autonomic nervous system (ANS) – both sympathetic and
parasympathetic responses. As an endocrine gland, it releases hormones that regulate the
secretion of other hormones involved in the stress response. This is why the hypothalamic
response to stress is often referred to as a neuroendocrine response.
Here is a bit more detail about the functions of the hypothalamus:




Receives input from higher brain centers in the cerebral cortex, limbic system and
reticular activating system (RAS)
Receives input from central and peripheral receptors re: physical and chemical changes
in blood or CSF (detects changes in blood and CSF chemistry, temperature and
pressures)
Regulates Autonomic NS function: relative balance of sympathetic (NE/epi) and
parasympathetic (ACh) release; some sympathetic signals are sent to locus ceruleus of
pons (LC/NE) which then secretes more NE to stimulate the target cell responses
Secretes hormones: CRH, TRH, GHRH, GnRH, ADH and OT which affect multiple target
organs, including other endocrine glands (such as the anterior and posterior pituitary)
Cerebral Cortex, Limbic System and Reticular Activating System influence
Hypothalamic Stress Responses
The cerebral cortex, limbic system, reticular activating system and hypothalamus are in
constant communication regarding changes in the internal or external environment.
Cerebral cortex – prefrontal region – conscious thought, logic, reasoning, motivation, behavior,
personality; stress can increase neural activity and create a state of hypervigilance, altered
cognition, behavioural changes and focused attention
Limbic system – innate survival; instinctive behaviors and responses

Hippocampus – (medial temporal lobe) - short and immediate memory and learning;
stress can affect these functions


Amygdala – memory and emotion (fear, anger, rage, excitement), including those
related to stressors
Note: stress can alter the normal amygdala and hippocampal functions
Reticular Activating System (RAS) – collection of CNS areas, including limbic structures
and thalamus; receives major sensory input from olfactory receptors; modulates mental
alertness, ANS activity and skeletal muscle tone and relays this information to the
hypothalamus and cerebral cortex (via thalamus); stress-induced overactivation
stimulates increased skeletal muscle tone (i.e. muscle tension)
Stress affects the ability of the cerebrum, limbic system, RAS and hypothalamus to
process information accurately. Think about this statement in relation to the effect of
stress on the individual’s ability to think clearly and remember accurately.
✓How might this affect the patient’s ability to provide an accurate patient history?
✓How might this affect a student’s ability to provide accurate test answers?
Notice the dual innervation of most organs.
A few organs have sympathetic innervation only: e.g. kidney (renin secretion to stimulate the
RAAS), adrenal medulla, (secretion of NE and epi), sweat glands (heat dissipation), adipose cells
(lipolysis for energy production), arrector pili smooth muscles (in dermis; make your hair stand
on end) and blood vessels (not clear cut here; may cause vasoconstriction or vasodilation,
depending on the organ).
A bit of ANS pharmacology:
Different drugs are classified as cholinergic or adrenergic stimulants because they mimic
parasympathetic or sympathetic effects on target organs, often by binding to the normal NT
receptor. The body cell thinks the drug is the normal NT and responds. These effects may be
classified as the side effects of the drug.
A drug that mimics the action of a normal body chemical (such as a NT or hormone) by binding
to its receptors is called an agonist of that body chemical. A drug that blocks the action of a
normal body chemical by binding to its receptors is called an antagonist of the body chemical.
Historical Background: the Physiology of the Stress Response
✖1914 Dr. Walter B. Cannon
+ Stress causes physiologic and/or psychologic strain on homeostatic balance; ‘fightor-flight’ response
✖1946 Dr. Hans Selye
+ General Adaptation Syndrome (GAS)
✖Stress is a non-specific biologic phenomenon resulting from an external or internal
environmental change in homeostasis
+ GAS is the neuroendocrine system response to stress
The concept of stress and its effects on the human body has been eluded to in medicine for
centuries.
Cannon and Selye are considered the modern ‘fathers’ of the study of the stress response and
the effects of stress on homeostasis.
Selye, a Canadian endocrinologist, even made the ‘cover’ of a postage stamp! (Look closely at
the chemical structure in the background - it is the stress hormone, cortisol.) Selye elaborated
on Cannon’s initial hypothesis and developed the term General Adaptation Syndrome (GAS) to
explain the neuroendocrine response to stress.
Selye proposed that two main factors would determine the nature of the individual’s response
to a specific stressor: 1) the specific event or environmental stressor (e.g. is this an acute event
or a chronic exposure to the stressor, and 2) the conditioning of the individual experiencing the
stress (e.g. internal factors such as genetic predisposition, age, gender or external factors such
as previous exposure, life experience, diet, social supports). This second factor includes the
ability of the individual to cope with the stressor.
The Stress Response and
The General Adaptation Syndrome
Think of the hare as the acute fight-or-flight rapid response and the tortoise as the slower, but
sustained resistance stage of a stress response.
Chronic activation of the resistance stage may lead to allostasis or even allostatic overload,
depending on other factors affecting the individual.
General Adaptation Syndrome (GAS)
General Adaptation Syndrome (GAS) describes the neuroendocrine response to
stress
+ 3 stages:
1. Alarm Reaction (fight – or – flight)
• Immediate hypothalamic neuroendocrine SNS mediated response to real or
perceived stress; all responses deemed vital to survival mobilized
2. Resistance Reaction (allostasis/adaptation)
• Stress continues; HPA activation →hypothalamic hormone secretion (CRH) to
keep body activated to survive the stress
3. Exhaustion stage (allostatic overload)
• Stress is continuing for prolonged period of time; body is running out of resources to
survive the stress; possible onset of stress-related issues
We will look at each stage individually.
General adaptation syndrome (GAS) was first described by a Canadian scientist named Hans
Selye in the 1930s. Notice that GAS has 3 stages.
The alarm stage is what you would have learned previously as the ‘fight-or-flight response.
Usually, this is the only response needed to return to homeostasis.
During prolonged stress responses, the alarm stage hypothalamic norepinephrine/epinephrine
mediated neural response is reinforced and maintained by the addition of the resistance
reaction hypothalamic endocrine responses, beginning with corticotrophin releasing hormone
(CRH) secretion. CRH initiates the hypothalamic-pituitary-adrenal (HPA) axis, i.e. the HPA
response to stress. The cerebral cortex and limbic systems are very sensitive to CRH, too.
Note: To describe an individual with a very pronounced sympathetic fight-or-flight response,
you will sometimes hear health professionals refer to that person as being in sympathetic
overdrive. I’ve heard the term used to describe crystal meth users’ manifestations. Be sure to
review the A and P of sympathetic NS responses. I will ask you about them.
General Adaptation Syndrome (GAS)
Alarm Stage FAST RESPONSE
+ IMMEDIATE neuroendocrine ‘fight or flight’ reaction to a stressor
1. 1) Hypothalamus →sympathetic division of ANS →catecholamines NE
→locus ceruleus (in pons) →more NE/epi (80%/20%)→target cells→F or F
response
2. 2) Hypothalamus →LC/NE →stimulates adrenal medulla →secretes
sympathomimetic hormones→Epi and NE (80%/20%) →target cells
→prolong F or F response
+ Physiological effects of norepinephrine/epinephrine
✖ Increased perfusion to organs vital to survival; those deemed nonvital to survival see their perfusion decreased ...outcomes?
+ Response time?
✖ Neural response – msec
✖ Hormonal response – minutes
In GAS, the alarm stage or alarm reaction is the immediate neurological and endocrine (i.e.
neuroendocrine) response to stress. It is also commonly called the fight-or-fight response.
The hypothalamus senses the stress and responds immediately (like a hare) via the sympathetic
division of the autonomic NS. (Some authors describe this as an increase in sympathetic tone or
sympathetic drive). The catecholamine neurotransmitters norepinephrine (NE) and
epinephrine (80%/20%, secreted respectively) are released by hypothalamic neurons and bind
to receptors on locus ceruleus (LC) cells of the pons. These pontine neurons release more NE
(often called the LC/NE system) which consequently binds to specific adrenergic receptors on
various effectors (target cells) stimulating a change in the function of these effectors.
The hypothalamic-LC/NE also stimulates the adrenal medulla to secrete even more
epinephrine and norepinephrine (as hormones 80/20%, respectively). These sympathomimetic
hormones will travel through the blood stream to stimulate distant target cells. The hormonal
response will be a bit slower, but will help to sustain the fight-or-flight response.
The alarm reaction evolved for survival, thus begins within milliseconds!
GAS: The Neuroendocrine Response to Stress
The entire HPA axis response during the alarm and resistance stages of GAS are shown in this
slide. You will see this slide more than once in this presentation and as a handout in the module
on the Learn site. Use it to answer question 7 of your worksheet.
We will work through this chart in class.
(a) Fight-or-flight (alarm) reaction: follow green arrows
(b) Resistance reaction (adaptation/allostasis): follow red and black arrows
(c) Exhaustion stage is a continuation of the resistance reaction which lasts until all of the
body’s resources have been depleted
Some questions for you! What are some of the immediate effects of SNS stimulation?
Visceral effectors are the target cells stimulated by NE/epi. For each of visceral effector,
indicate
whether there the stress response causes an increase or a decrease in activity or size: Heart
rate? Force of cardiac muscle contraction (contractility)? BP?
Pupil size? Respiration rate? Blood glucose level? Insulin secretion?
Blood vessel diameter – the response is different here and reflects the survival needs of the
body. Vital to survival organs receive extra blood supply (extra nutrients to produce the energy
needed for immediate survival of the stress); those deemed non-vital receive less blood flow
(not essential to the survival of a stressful event). For each of the blood supplies below choose
whether the local arteries will dilate or constrict: (Need help? Any A and P or Pathophysiology
text has the answers to these questions) in coronary arteries? in cerebral arteries? in skeletal
muscle arteries? in pulmonary arteries? in renal arteries? in digestive arteries?
Now think about the effects of prolonged stress on those organs whose blood supply
decreased.
Alarm Stage: Fight-or-Flight Responses
Compare this slide to the earlier one that compared normal sympathetic and parasympathetic
physiologic actions.
Can you relate these clinical manifestations to sympathetic nervous system’s physiologic stress
responses?
Dry mouth
Pale (pallor), shiver ‘feel cold’, cold hands and feet Rapid, bounding pulse
Stomach upset/indigestion/lack of appetite Twitchy or sore muscles, shakiness, trembling
Complaints about bright lights (e.g. in the ER) Rapid almost gasping breathing
Dilated pupils
Indigestion/constipation – although if stress has made it difficult to digest food in the gut, you
may manifest with diarrhea first (undigested foods in the large intestine cause irritation,
bloating and diarrhea)
Headaches, angina, TIAs
Now go back a few slides and compare these responses to the physiological effects of
stimulation of the sympathetic NS.
General Adaptation Syndrome (cont’d)
2. Resistance (Adaptation) Stage S L O W E R
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+ Additional neuroendocrine adaptation to prolonged stress
+ Helps to maintain mobilized defenses; keep the stress response going,
although probably at a slightly lower activity level
+ ActivationoftheHPAaxis→hormonessecreted→target organs respond
+ What is the HPA axis?
✖ 3 endocrine glands →3 hormones

✖ Hypothalamus→Anterior Pituitary→Adrenal Cortex
CRH →ACTH →Cortisol (Corticotrophin Releasing
Hormone) (Adrenocorticotropic Hormone) (Glucocorticoid)

+ Response time? Min/hours/days/weeks...
The resistance (or adaptation) stage is a secondary neuroendocrine response to stress that is
stimulated if the stress is lasting longer than a few minutes. The hypothalamus is still in charge;
the response begins with the secretion of hypothalamic hormones which stimulate the
subsequent secretion of pituitary hormones and adrenal gland hormones. This neuroendocrine
response is known as the hypothalamic-pituitary-adrenal axis, the HPA. You will hear about
the HPA many times in the nursing program!
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How does the HPA work?
Hypothalamic neuroendocrine cells in a region called the paraventricular nucleus (PVN)
secrete a hormone called corticotrophin releasing hormone (CRH; aka corticotrophin
releasing factor, CRF). CRH travels through the blood stream to its target cells in the
anterior pituitary gland. The anterior pituitary responds to CRH stimulation by secreting
adrenocorticotrophichormone(ACTH). ACTH travels through the blood stream to the
adrenal cortex, stimulating the release of the glucocorticoid, cortisol. The CRH
→ACTH→cortisol response to stress forms the HPA axis. CRH also stimulates the
cerebral cortex and limbic system responses to stress. The SNS is also still in overdrive,
inundating the adrenal medulla with signals to continue to secrete epinephrine and
norepinephrine. All that transport of hormones takes time (like a slower tortoise) to
travel through the blood stream to its target cells but can stay active for a long time.
The resistance stage begins in minutes to hours and can last for days, months, even
years as long as the body keeps supplying the resources (glucose, energy, proteins,
lipids) to make the hormones. This resistance stage is also called the adaptation stage
and can result in a change to the hypothalamic set point i.e. allostasis to occur.
Hypothalamic-Pituitary-Adrenal Axis (HPA)
❖Cortisol is the major stress hormone made by the adrenal
cortex. Since the adrenal medulla makes epinephrine and
norepinephrine – also major stress hormones, the entire adrenal
gland is often called the stress gland.
Cortisol is a glucocorticoid, a steroid hormone made by the
adrenal cortex that affect blood glucose levels. (can you see how the name was derived?) When
the body is under stress, cellular energy consumption increases in all the cells that are
stimulated to respond to stress (those vital organs). One of the major metabolic effects of
cortisol is to mobilize energy stores to increase blood glucose. Thus, stress causes increased
cortisol which leads to increased blood glucose (i.e. excessive cortisol has a hyperglycemic
effect). Note: this is also why prolonged stress from any cause can exacerbate manifestations in
a patient with Type 1 or Type 2 DM.
The HPA is a negative feedback system. Thus the physiological effects of the increased release
of a particular hormone should feed back to the initial hormonal regulator (in this case the
hypothalamus) to decrease its release once the desired physiological effects have achieved the
desired homeostatic balance. During normal everyday body functioning, once the desired
cortisol physiological responses have occurred, the hypothalamus would decrease its release of
CRH and subsequently decrease the levels of ACTH and cortisol back to normal. But, if the
individual is in a state of constant real or perceived stress, the hypothalamus keeps the HPA axis
active and the cortisol levels and BG levels remain high. In addition, during prolonged stress,
CRH from other peripheral sources (such as immune cells) also stimulate cortisol.
For a review of the negative feedback system and its components refer to the Handout:
Overview of Negative Feedback Regulation of Homeostasis posted on the Learn site.
Feedback Control of Glucocorticoid Synthesis and Secretion
Role of the HPA and other Hormones in the
Stress Response
Now we add in the resistance reactions that occur
during longer term response to stressors; the
resistance reactions begin while the alarm reactions
continue (albeit probably at a lower level of activity)
(b) Resistance reaction (aka allostasis)
Red to black arrows: the neuroendocrine resistance
reactions, including the HPA axis as well as the
release of other hypothalamic→pituitary→thyroid or
liver hormonal pathways that help to sustain the energy needs of the visceral effectors that are
trying to survive the stress. Notice that in the resistance reactions, the HPA axis (i.e.
CRH→ACTH→cortisol) is aided by several other hormone secretion pathways:
GHRH→hGH→IGFs, TRH→TSH→T3/T4 (thyroid hormones) and by epinephrine’s direct
stimulation of glucagon secretion by the pancreas (glucagon stimulates the liver to release
glucose from storage). ALL help to increase blood glucose levels.
The exhaustion stage would simply continue the resistance reaction effects over a longer time
frame, until all resources are depleted.
General Adaptation Syndrome (GAS)
Exhaustion stage (allostatic overload)
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+ Continued stress leads to breakdown
of compensatory body defenses
+ Marks onset of disease processes,
illness →watch for CV, neural, renal and
immune adaptations
+ Occurs only if stress continues and
adaptation is not successfu
Sorry – can’t resist a cute bunny picture!
Sometimes body tissues are unable to recover from a severe or prolonged stress and
enter the exhaustion stage. The cells have used up their resources and are really
struggling to survive. Chronic stress and chronic neuroendocrine overstimulation can
manifest in psychological, neurological or immunological ways. The individual is now in
allostatic overload.
Think about the effects of NE/epi and cortisol on body tissues. What happens when
these neurotransmitter/hormone levels remain abnormally high? How do the tissues
adapt?
For example, chronic hyperglycemia has a variety of detrimental effects on body cells –
e.g. damages endothelial cells lining blood vessels, increases BP and decreases WBC
function.
Think of some chronic disorders that are thought to be exacerbated by stress.
Refer to Table 11.1 of your text for more examples. Can you relate these stress- related
disorders to dysregulation of the normal stress response? Remember that the ability of
the body to withstand a stressor is individualized, so different people will manifest
differently to a specific stressor.
How Does Chronic Stress Precipitate Disease?
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Time to link the neuroendocrine response to stress to increased risk of stress-related
disease.
Look for the normal roles of norepinephrine, epinephrine and cortisol and then think
about what would happen if these hormones levels did not return to homeostatic levels
resulting in dysregulation of neural, endocrine and/or immune function.
Psycho Neuro Immunology (PNI)
You have probably heard that being stressed makes you more prone to illness.
Researchers have noted a strong interrelationship between neural, endocrine and
immune function, called the Psychoneuroimmunology (PNI) relationship. Alterations of
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one system often affects the normal function of the other systems. The PNI relationship
helps to explain why perceived or real stressors can make us feel sick and keep us sick
by triggering the stress response, especially the release of cortisol. We will look at the
relationship of the PNI to stress-related diseases. Chronic stress causes dysregulation of
the neuroendocrine HPA axis leading to abnormal and prolonged elevation of cortisol
levels. Cortisol is a key mediator of the body’s physiological stress responses, including
the immune defense.
Here are 2 examples of the PNI in action:
1) Acute stress effects: Individual develops a cold→HPA activated→stimulates slight
increase in cortisol levels→cortisol’s proinflammatory effects promote acute
inflammatory response→innate WBC destruction of microbes→individual feels better
2) Chronic stress effects: RRC nursing student→stressful assignment(s)→trouble
sleeping→disrupts the body’s normal circadian rhythm→HPA chronically
activated→stimulates prolonged increase in cortisol levels→cortisol’s antiinflammatory effects suppress acute inflammatory response; immune system function
decreases →friends/family have a cold→student develops sniffles and
sneezes→ignores symptoms →cortisol levels rise a bit more→can’t seem to ‘shake’ that
cold... and still feeling sleep deprived....
To explain this interrelationship, we need to look at some specific effects of stress on
the functioning of the Nervous System, the Endocrine System and the Immune System.
Watch for the roles of the HPA in this section!
Stress response
This is quite
the flow chart
for explaining
the stress
response!
Could actually
lead to some
stress in the
person
studying it!
Follow the
chart in
coloured
sections. You
will notice
some overlap
with the
previous slide.
As you follow
the chart, think about the clinical significance of some of the physiological effects. I will make
some of those links for you as you keep reading.
Start with the SNS (in blue). [Note: I have added in an extra blue line connecting hypothalamus
to SNS response]. Notice that norepinephrine and epinephrine have different physiological
effects based upon the specific adrenergic receptors they bind to on their target cells.
Reminder: The HPA consists of 3 main hormones: CRH→ACTH→cortisol
The release of CRH (in pink) starts the HPA axis that helps prolong the initial SNS response.
CRH also increases activity of the LC/NE system, leading to the release of more NE.
Which organs are affected by NE stimulated arteriolar smooth muscle contraction (i.e.
vasoconstriction).
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Kidneys: a decrease in renal blood flow stimulates renal secretion of renin, triggering
activation of the RAAS renin→aldosterone→angiotensin system.
Angiotensin II is a potent vasoconstrictor which can cause systemic vasoconstriction in
many organs, such as the cerebral or coronary arterioles. Notice that epinephrine
simultaneously increases cardiac workload. That can’t be good long term.
• Aldosterone stimulates renal sodium retention and potassium excretion, which could affect F
and E balance.
Yellow illustrates the effect of CRH on the anterior pituitary ACTH release but also shows the
effects of CRH on the release of antidiuretic hormone (ADH) from the posterior pituitary. ↑ADH
secretion stimulates the kidneys to increase tubular reabsorption of water (i.e. water
retention), leading to an increase in blood volume. ↑ BV is a cause of ↑BP (we will elaborate
on this relationship in the cardiovascular pathophysiology module). Remember, epinephrine
and NE simultaneously ↑ heart rate and contractility and stimulate systemic arteriole
vasoconstriction, all of which also cause ↑ BP. Now look for the effects of epinephrine on the
liver and adipose tissue. Stress increases blood lipid and blood glucose levels by pulling them
out of long term storage (via lipolysis and glycogenolysis and using them to create new glucose,
a process called gluconeogenesis) – what are some long term effects of these adipose and
glucose homeostatic imbalances?
Finally, look to the green area for cortisol’s effects. More increased BP, some atrophy of the
immune tissue that could cause decreased innate inflammatory and wound healing responses.
Depending on the time frame and the amount of cortisol secreted, cortisol may cause the
release of proinflammatory or anti-inflammatory cytokines, which in turn have different effects
in different tissues. Ultimately, sustained higher than normal levels of cortisol will alter WBC
function (called immune dysregulation) making the individual more susceptible to infections,
slowing down healing processes and may also increase their risk of hypersensitivity (increased
mast cell activity) or autoimmune (increased antibody responses) disorders.
Notice that cortisol can also affect ovarian and testicular function, causing menstrual and
fertility problems.
Notice that epinephrine, cortisol and CRH can all stimulate histamine release from mast cells.
Excessive histamine can potentially trigger exaggerated inflammatory responses seen in allergic
reactions (such as dermal rashes or itchiness) while also altering production of specific
cytokines, causing decreased cytotoxic and phagocytic responses.
Chronically elevated epinephrine and NE also alter cytokine signals and inhibit normal Th1, NK
and macrophage activity, suppressing the innate and cellular immune defenses to infections
while potentially increasing humoral (B cell antibody mediated) responses.
End results of chronic CRH mediated stimulation of higher than normal cortisol levels on
immune function?
• Causes dysregulation of immune cytokines which may lead to:
• Increased risk of exaggerated inflammatory responses predisposing the individual to allergies
or adaptive (antibody mediated) hypersensitivity or autoimmune reactions, and/or
• Decreased innate phagocytic or adaptive cytotoxic T cell cellular mediated destruction foreign
agents such as viral infections or newly developed tumour cells.
• Recall that being a stressed student can make you sick more often
Cortisol: anti-inflammatory or pro- inflammatory mediator? Both!
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❖ Cortisol may have
proinflammatory or anti-inflammatory
effects, depending on source, location
and duration of its secretion
❖ As Tx? Prednisone &
hydroxycortisone are used as antiinflammatory drugs
❖↓ T cell and innate immune
responses ...but don’t use too much

❖ During acute (short term)
stress response? E.g. tissue damage
❖Local effects
❖Proinflammatory: activates innate immune responses →acute
inflammatory response →wound healing →no deficits ☺❖During chronic
(prolonged) stress response?
❖Systemic effects

❖ Anti-inflammatory: ↓ Th1 function →↓ T cell and innate immune
responses→↓ immune response to infections, neoplasms

❖ Pro-inflammatory: 1) ↑Th2 function →↑ B cell responses →↑ risk of
hypersensitivity & autommune disorders and 2) ↑ mast cell degranulation→↑
histamine effects→↑ risk of allergic responses
Individuals experience multiple stressors every day. Homeostatic mechanisms are constantly
adjusting to stressors. Keep in mind that acute stress and a rapid alarm reaction is a normal
physiological response to a stressor which mobilizes body systems to respond to the stressor.
That response includes enhancing immune function. This is logical since tissue damage is a
physiological stressor that requires a pro-inflammatory response to destroy the causative agent
and promote wound healing.
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Chronic stress, with its abnormal HPA response dysregulates this axis and alters normal
immune function by changing the responses of mast cells, B cells and T cells. That is why
some anti-inflammatory and some pro-inflammatory effects occur.
Pharmacological note: long term use of prednisone (i.e. cortisol) causes side effects
similar to the systemic effects in this slide.
Note:
Th1 helper T cells release cytokines that activate cytotoxic T cells, NK cells and
macrophages.
Th2 helper T cells release cytokines that activate B cells to undergo morphological
change, become plasma cells and then begin secreting antibodies.
Effects of chronic stress on wound healing
What is the effect of chronically dysregulated
psychoneuroimmune response on wound healing?
Hint: The individual dealing with multiple stressors may find
themselves in allostatic overload.
✓Are they sick less often or more often?
✓Does the person stay sick longer than usual?
The effects of chronic stress and resultant elevated blood cortisol decreases the rate at which
wounds heal by altering WBC function. The increased sympathetic NS activity affects tissue
perfusion, decreasing nutrient supply to damaged tissues.
Stress Interactions are Non-linear and Affect Many Body Systems
We know that chronic dysregulation of the HPA axis due to prolonged stress leads to chronically
elevated cortisol levels. Notice that there are elevated cortisol can cause both physiological
effects and psychological effects. These effects are non-linear, which means that the body’s
response to the stressor may change dependent on other variables. Remember allostasis - the
effects of stress and the body’s means of adapting to stressors is individualized.
Notice also the number of body systems and stress-related diseases listed on this slide. The
specific manifestations depend on the individual. Remember that allostatic adaptations and the
development of allostatic overload are individual effects.
Stress related diseases and conditions
Stress personality coping and illness
So what can be done to promote health in individuals living in a chronically stressed
environment? What is/are the possible health outcome(s) of the individual exposed to chronic
stress? How does the individual cope with the homeostatic imbalance resulting from a stressful
event? Remember, individuals have varied cognitive, behavioural and physiological responses
to stress.
Coping – mechanisms by which the individual applies psychological and behavioural processes
to manage a stressful event that is perceived as overstretching the normal reserves of the
individual; can the individual easily adapt?
The inability to cope with the new challenge, the chemical, physical or psychological stressor,
may affect the individual’s behavior and personality and may affect the outcome of the stress.
Does the stressor prolong a normally short-term illness or distress? Does the stressor
exacerbate a previously existing condition? Does the patient agree with the medical treatment
if one is suggested?
A. An otherwise healthy individual’s body should be able to cope with the stress; possible short
term illness and then a return to normal homeostasis and good health
2. An individual with a pre-existing condition may see an exacerbation of that condition or
be able to return to relatively good health
3. How the individual responds to medical intervention for a serous illness is determined
to some extent by the individuals perception of the treatment as a new stressor.
1. What are the 3 stages in Selye’s General Adaptation Syndrome (GAS)?
1) Alarm Reaction (fight – or – flight)
2) Resistance Reaction (adaptation)
3) Exhaustion stage (allostatic overload)
2. Define the term stress and state the 3 major categories of stressors.
Stress is commonly defined as a state of real or perceived threat to internal or external
homeostasis – eustress vs distress
3 major categories of stressors: physical, chemical and psychological
3. The body’s reactions to stress require both neural and endocrine responses – a
neuroendocrine stimulation. The Hypothalamic-Pituitary-Adrenal (HPA) Axis is a major
regulator of the stress response. Explain the role of the HPA Axis in the physiological
manifestations of stress (i.e. what happens during the General Adaptation Syndrome; GAS).
 Stressors are detected by the cerebral cortex, limbic system or hypothalamus of the brain.
The hypothalamus of the brain is particularly sensitive to changes in homeostasis; this
region is so important in the stress response that the other 2 brain components will relay
the problem to this area if they are stimulated first!
 Hypothalamic neural regulation is a rapid response via the sympathetic division of the
autonomic nervous system. This is known as the fight-or- flight response or the alarm
stage of Selye’s General Adaptation Syndrome. Two catecholamine neurotransmitters,
norepinephrine and epinephrine are responsible for stimulating many visceral effectors
during the stress response. Notice that these neurotransmitters also directly stimulate the
adrenal medulla (an endocrine gland) to secrete more epinephrine and norepinephrine,
slower acting hormones that help to maintain the fight-or-flight response. When secreted
as hormones from the adrenal medulla, epi and NE are called sympathomimetic. Why?
Physiological effects mimic those of the sympathetic NS.
 The hypothalamus also stimulates an endocrine response to stress. This endocrine
regulation is slower acting (because hormones need to travel through the blood stream to
their target cells and that takes time) and involves secretion of several hypothalamic
releasing hormones which then stimulate the release of a variety of anterior pituitary
hormones. These anterior pituitary hormones then stimulate several other target
endocrine glands to secrete their hormones. This final group of hormones binds to
receptors on the visceral effectors, eliciting the body’s reactions to the stressor.

The HPA axis hormones have the most dramatic effects on the stress responses.
o Name the 3 endocrine glands of the HPA axis and the specific hormones they
secrete:
o Endocrine Gland
Hormone Produced
_Hypothalamus
CRH
Anterior Pituitary
Adrenal gland
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ACTH
Cortisol
The adrenal gland is called the stress gland, because it produces both epinephrine and
cortisol. Cortisol, is a steroid hormone made by the adrenal cortex and epinephrine is a
catecholamine made by the adrenal medulla.
In addition to the HPA, during the resistance stage of stress, the hypothalamus may also
begin secreting 2 other releasing hormones that increase cell metabolic rates and blood
glucose levels. Growth hormone releasing hormone (GHRH) will stimulate the secretion
of growth hormone (hGH) from the anterior pituitary, which then stimulates the liver to
secrete IGFs. IGFs then direct the release of glucose from the liver. Hypothalamic
thyroid releasing hormone (TRH) will stimulate the release of TSH from the anterior
pituitary, which then stimulates the release of T3 and T4 from the thyroid gland. At the
same time, the continued epinephrine secreted from the adrenal medulla stimulates the
release of glucagon from the pancreas, which exacerbates the effects of the IGFs. Whew!
The slower acting HPA response to stress forms the resistance reaction of GAS and can
last hours, days, months or even years as long as the resources to run the HPA and other
endocrine responses are available to the body. If the reserves fail, and the body cannot
adapt, the body enters the exhaustion stage. During this final stage, clinical
manifestations of disease are expected.
4. Define allostasis: adaptive physiological response to stress (Fig. 11.5; text p.344)
5. Define adaptation: the processes by which the body survives the stress and returns to
homeostasis
6. Allostatic overload leads to the exhaustion stage of GAS. What is allostatic overload? What
are some clinical effects of severe allostatic overload (severe exhaustion stage of
physiological stress)? Read p. 344 of your text and review the slide of Fig. 11.5 in the lecture
presentation. Allostatic overload leads to the development of stress-related diseases.
7. Use the handout: Neuroendocrine Regulation of the Stress Response, Fig. 11.2 and the
tables in Chapter 11 of your text to complete the chart and questions re: HPA and the stress
response.
a) Complete the chart on the role of HPA hormones in the stress response.
Hormone
Site of
Physiological Effects
Production
Corticotropin Releasing Hormone
Hypothalamus Stimulates ACTH secretion
(CRH)
Adrenocorticotropic Hormone
(ACTH)
Ant. Pituitary
Stimulates cortisol secretion
Cortisol (glucocorticoids)
Adrenal cortex
Major stress hormone; see handout
Growth Hormone Releasing
Hormone (GHRH)
Growth Hormone (hGH)
Hypothalamus
Stimulates secretion of hGH
Ant. Pituitary
Insulin-like Growth Factor (IGF)
Liver
Thyroid Releasing Hormone (TRH)
Hypothalamus
Increases protein synthesis, stimulates
secretion of IGF; increases BG; see
handout
Stimulates liver to release glucose from
storage; increases BG (hyperglycemic
effect)
Stimulates secretion of TSH
Thyroid Stimulating Hormone
(TSH)
Ant. Pituitary
Stimulates secretion of thyroid hormones
Thyroid Hormone T3 and T4
Thyroid gland
Antidiuretic Hormone (ADH)
Hypothalamus
Epinephrine and Norepinephrine
Hypothalamus
and adrenal
medulla
Pancreas
Increase basal metabolic rate; increases
BG; see handout
Stimulates water reabsorption (retention)
by kidneys; F and E balance
Major stress hormones; see handout
Glucagon
Stimulates liver to release glucose from
storage (as glycogen); increases BG
b) Which stress hormone(s) affect blood glucose levels?
o Glucagon, epinephrine, cortisol, IGFs (following GH stimulation), thyroid
o What is the common effect of the HPA stress hormones on blood glucose (BG)
levels? ↑ or ↓ BG causing ___________________
(hypoglycemia/hyperglycemia).
o What is the clinical significance of this change in blood glucose levels during
stress? Pt may present with DM-like manifestations
c) Which stress hormone(s) affect immune function?
o cortisol
o Is this a proinflammatory or anti-inflammatory effect? Depends:– acute = antiinflammatory, chronic = proinflammatory
o What is the clinical significance of this change in immune function during stress?
Pt at greater risk of prolonged infections and poorer wound healing
d) Which stress hormone(s) affect blood pressure?
o Epinephrine and norepinephrine
o Does stress ↑ or ↓ blood pressure? Causes systemic arterial vasoconstriction.
e) Which stress hormone(s) affect your blood volume?
o Epinephrine and norepinephrine
o Does stress ↑ or ↓ blood volume? _promotes water retention by decreasing renal
function
o Does this effect ↑ or ↓ blood pressure?
f) Which stress hormone(s) affect your cardiac output? (Hint: they affect heart rate or stroke
volume)
o Epinephrine and norepinephrine
o Does stress ↑ or ↓ cardiac output? By increasing heart rate and stroke volume.
o Does this effect ↑ or ↓ blood pressure?
o What is the clinical significance of this change in cardiac output during stress?
Stress increases risk of hypertension
g) Which stress hormone(s) affect your arteriole smooth muscle?
o Which stress hormone(s) affect your arteriole smooth muscle? Epinephrine and
norepinephrine
o Does stress stimulate arteriolar vasoconstriction or vasodilation? Depends on the
body part – is it vital to the fight-or-flight survival of the stressor?
 In cerebral arterioles? vasodilation
 In cardiac arterioles? vasodilation
 In pulmonary arterioles? vasodilation
 In skeletal muscle arterioles? vasodilation
 In renal arterioles? vasoconstriction
 In digestive arterioles? vasoconstriction
 In dermal arterioles? vasoconstriction
o Does this overall effect on arterioles ↑ or ↓ blood pressure? By increasing
systemic vascular resistance
o What is the clinical significance of these changes in arteriole diameter during
stress?
pt at increased risk of hypertension
Module 3 ends