Innate Immunity:
Inflammation
Chapter 6
1
Immunity

First line of defense


Second line of defense


Innate resistance
Inflammation
Third line of defense

Adaptive (acquired) immunity
2
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First Line of Defense

Physical and mechanical barriers


Skin
Linings of the gastrointestinal, genitourinary, and
respiratory tracts





Sloughing off of cells
Coughing and sneezing
Flushing
Vomiting
Mucus and cilia
3
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First Line of Defense

Biochemical barriers


Synthesized and secreted saliva, tears, earwax,
sweat, and sebum
Antimicrobial peptides


Cathelicidins, defensins, and collectins
Normal bacterial flora
4
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Second Line of Defense

Inflammatory response

Caused by a variety of materials



Infection, mechanical damage, ischemia, nutrient
deprivation, temperature extremes, radiation, etc.
Local manifestations
Vascular response

Blood vessel dilation, increased vascular permeability
and leakage, white blood cell adherence to the inner
walls of the vessels and migration through the vessels
5
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Inflammation

Goals




Limit and control the inflammatory process
Prevent and limit infection and further damage
Interact with components of the adaptive immune
system
Prepare the area of injury for healing
6
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Plasma Protein Systems

Protein systems




Complement system
Coagulation system
Kinin system
All contain inactive enzymes (proenzymes)

Sequentially activated


First proenzyme is converted to an active enzyme
Substrate of the activated enzyme becomes the next
component in the series
7
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Plasma Protein Systems

Complement system



Can destroy pathogens directly
Activates or collaborates with every other
component of the inflammatory response
Pathways



Classical
Lectin
Alternative
8
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Plasma Protein Systems

Coagulation (clotting) system

Forms a fibrinous meshwork at an injured or
inflamed site





Prevents the spread of infection
Keeps microorganisms and foreign bodies at the site
of greatest inflammatory cell activity
Forms a clot that stops bleeding
Provides a framework for repair and healing
Main substance is an insoluble protein called
fibrin
9
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Plasma Protein Systems

Kinin system



Functions to activate and assist inflammatory
cells
Primary kinin is bradykinin
Causes dilation of blood vessels, pain, smooth
muscle contraction, vascular permeability, and
leukocyte chemotaxis
10
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Plasma Protein Systems
11
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Plasma Protein Systems
12
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Cellular Mediators of Inflammation

Cellular components


Granulocytes, platelets, monocytes, and
lymphocytes
Cell surface receptors





Pattern recognition receptors (PRRs)
Pathogen-associated molecular patterns (PAMPs)
Toll-like receptors
Complement receptors
Scavenger receptors
13
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Mast Cells

Cellular bags of granules located in the loose
connective tissues close to blood vessels


Skin, digestive lining, and respiratory tract
Activation


Physical injury, chemical agents, immunologic
processes, and toll-like receptors
Chemical release in two ways

Degranulation and synthesis of lipid-derived chemical
mediators
14
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Mast Cell Degranulation

Histamine



Vasoactive amine that causes temporary, rapid
constriction of the large blood vessels and the
dilation of the postcapillary venules
Retraction of endothelial cells lining the
capillaries
Receptors


H1 receptor (proinflammatory)
H2 receptor (anti-inflammatory)
15
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Histamine

Receptors

H1 receptor



Proinflammatory
Present in smooth muscle cells of the bronchi
H2 receptor


Anti-inflammatory
Present on parietal cells of the stomach mucosa

Induces the secretion of gastric acid
16
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Mast Cell Degranulation

Chemotactic factors

Neutrophil chemotactic factor


Attracts neutrophils
Eosinophil chemotactic factor of anaphylaxis
(ECF-A)

Attracts eosinophils
17
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Mast Cell Synthesis of Mediators

Leukotrienes



Prostaglandins


Product of arachidonic acid from mast cell
membranes
Similar effects to histamine in later stages
Similar effects to leukotrienes; they also induce
pain
Platelet-activating factor

Similar effect to leukotrienes and platelet activation
18
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Mast Cells
19
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Mast Cells
20
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Mast Cells
21
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Phagocytosis



Process by which a cell ingests and disposes
of foreign material
Production of adhesion molecules
Margination (pavementing)


Adherence of leukocytes to endothelial cells
Diapedesis

Emigration of cells through the endothelial
junctions
22
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Phagocytosis
23
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Phagocytosis

Steps





Opsonization, recognition, and adherence
Engulfment
Phagosome formation
Fusion with lysosomal granules
Destruction of the target
24
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Phagocytes

Neutrophils




Also referred to as polymorphonuclear
neutrophils (PMNs)
Predominate in early inflammatory responses
Ingest bacteria, dead cells, and cellular debris
Cells are short lived and become a component of
the purulent exudate
25
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Phagocytes

Monocytes and macrophages



Monocytes are produced in the bone marrow,
enter the circulation, and migrate to the
inflammatory site, where they develop into
macrophages
Macrophages typically arrive at the inflammatory
site 3 to 7 days after neutrophils
Macrophage activation results in increased size,
plasma membrane area, glucose metabolism,
number of lysosomes, and secretory products
26
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Monocytes and Macrophages
27
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Phagocytes

Eosinophils


Mildly phagocytic
Duties

Defense against parasites and regulation of vascular
mediators
28
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Phagocytes

Natural killer (NK) cells


Function is to recognize and eliminate cells
infected with viruses and some function in
eliminating cancer cells
Platelets

Activation results in degranulation and interaction
with components of the coagulation system
29
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Cytokines

Interleukins



Produced primarily by macrophages and
lymphocytes in response to a pathogen or
stimulation by other products of inflammation
Many types
Examples


IL-1 is a proinflammatory cytokine
IL-10 is an anti-inflammatory cytokine
30
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Cytokines

Interferon



Protects against viral infections
Produced and released by virally infected host
cells in response to viral double-stranded RNA
Types

IFN-alpha and IFN-beta


Induce production of antiviral proteins
IFN-gamma

Increases microbiocidal activity of macrophages
31
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Cytokines
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Cytokines

Tumor necrosis factor–alpha

Secreted by macrophages in response to PAMP
and toll-like receptor recognition



Induces fever by acting as an endogenous pyrogen
Increases synthesis of inflammatory serum proteins
Causes muscle wasting (cachexia) and intravascular
thrombosis
33
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Cytokines
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Local Manifestations of Inflammation

Results from vascular changes and
corresponding leakage of circulating
components into the tissue




Heat
Redness
Swelling
Pain
35
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Exudative Fluids

Serous exudate


Fibrinous exudate


Thick, clotted exudate: indicates more advanced
inflammation
Purulent exudate


Watery exudate: indicates early inflammation
Pus: indicates a bacterial infection
Hemorrhagic exudate

Exudate contains blood: indicates bleeding
36
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Systemic Manifestations of
Inflammation

Fever



Leukocytosis


Caused by exogenous and endogenous pyrogens
Act directly on the hypothalamus
Increased numbers of circulating leukocytes
Increased plasma protein synthesis

Acute-phase reactants

C-reactive protein, fibrinogen, haptoglobin, amyloid,
ceruloplasmin, etc.
37
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Chronic Inflammation



Inflammation lasting 2 weeks or longer
Often related to an unsuccessful acute
inflammatory response
Other causes of chronic inflammation:




High lipid and wax content of a microorganism
Ability to survive inside the macrophage
Toxins
Chemicals, particulate matter, or physical irritants
38
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Chronic Inflammation
39
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Chronic Inflammation

Characteristics




Dense infiltration of lymphocytes and
macrophages
Granuloma formation
Epithelioid cell formation
Giant cell formation
40
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Resolution and Repair


Regeneration
Resolution


Returning injured tissue to the original structure
and function
Repair


Replacement of destroyed tissue with scar tissue
Scar tissue

Composed primarily of collagen to restore the tensile
strength of the tissue
41
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Resolution and Repair

Débridement


Cleaning up the dissolved clots, microorganisms,
erythrocytes, and dead tissue cells
Healing



Filling in the wound
Sealing the wound (epithelialization)
Shrinking the wound (contraction)
42
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Healing

Primary intention


Wounds that heal under conditions of minimal
tissue loss
Secondary intention

Wounds that require a great deal more tissue
replacement

Open wound
43
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Healing

Reconstructive phase




Fibroblast proliferation
Collagen synthesis
Epithelialization
Contraction


Myofibroblasts
Cellular differentiation
44
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Healing

Maturation phase



Continuation of cellular differentiation
Scar tissue formation
Scar remodeling
45
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Healing
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Dysfunctional Wound Healing

Dysfunction during inflammatory response








Hemorrhage
Fibrous adhesion
Infection
Excess scar formation
Wound sepsis
Hypovolemia
Hypoproteinemia
Anti-inflammatory steroids
47
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Dysfunctional Wound Healing

Dysfunctional during reconstructive phase

Impaired collagen matrix assembly



Impaired epithelialization


Keloid scar
Hypertrophic scar
Anti-inflammatory steroids, hypoxemia, and
nutritional deficiencies
Impaired contraction

Contracture
48
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Dysfunctional Wound Healing
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Dysfunctional Wound Healing

Wound disruption

Dehiscence

Wound pulls apart at the suture line


Excessive strain and obesity are causes
Increases risk of wound sepsis
50
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Pediatrics




Neonates have transiently depressed
inflammatory and immune function
Neutrophils are not capable of efficient
chemotaxis
Neonates express complement deficiency
Deficient in collectins and collectin-like
proteins
51
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Elderly

Impaired inflammation is likely a result of
chronic illness




Diabetes, cardiovascular disease, etc.
Chronic medication intake decreases the
inflammatory response
Healing response is diminished due to loss of
the regenerative ability of the skin
Infections are more common in the elderly
52
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