University of Colorado Denver – School of Medicine
Disease and Defense Course IDTP5004A
Instructor: Francisco G. La Rosa, MD, Associate Professor
February 5th, 2010
ACUTE AND CHRONIC INFLAMMATION
Recommended Reading: Chapter 2 - "Acute and Chronic Inflammation", in Kumar, Robbins and
Cotran: Pathologic Basis of Disease, 8th ed. WB Saunders Co. This is also available free
online at: http://www.mdconsult.com/das/book/body/94286448-2/0/1249/0.html
Learning Objectives:
1.
List and describe the 5 clinical signs of acute inflammation and give their clinicalpathogenetic basis.
2.
Describe the 3 major pathogenetic mechanisms of acute inflammation. Summarize the role
of the endothelial cell.
3.
List and describe the sequence of events involving a neutrophilic response in acute
inflammation due to a pyogenic microorganism, e.g. Staphylococcus aureus.
4.
Discuss leukocyte and endothelial cell adhesion molecules and cite an example of each.
5.
Define chemotaxis and list the 3 major examples.
6.
Define opsonin and list the 2 major types.
7.
Describe the process by which a neutrophil engulfs and destroys a pyogenic
microorganism.
8.
Define and compare transudate and exudate. List and describe the different types of
exudate citing etiologic agents for each type.
9.
Define and compare abscess and cellulitis.
10. Define chronic inflammation and compare it to acute inflammation. Give examples of
etiologic agents of chronic inflammation.
11. Indicate the features and differential diagnosis of granuloma. Discuss its pathogenesis.
12. Define and compare ulcer and erosion.
13. Define and compare fistula and sinus tract.
14. Describe the pathogenetic, pathologic and clinical features of leukocyte adhesion
deficiency, type I; chronic granulomatous disease of infancy, and Chediak-Higashi disease.
15. Define and indicate the major features of the systemic inflammatory response syndrome
and the acute phase reaction.
16. Describe sarcoidosis.
Disease & Defense Block
I.
“Acute and Chronic Inflammation”
Page 2
ACUTE INFLAMMATION
A. CLINICAL FEATURES:
Celsus, a Roman writer of the first century AD, first listed the four cardinal signs of
inflammation:
1. Rubor (Redness)
2. Calor (Warmth)
3. Tumor (Swelling)
4. Dolor (Pain)
5. Functio laesa (Loss of function) (later added by Virchow).
B. PATHOGENESIS: Three main processes occur at the site of inflammation, due to the
release of chemical mediators:
1. Increased blood flow. Brief initial vasoconstriction (pallor) is followed by vasodilatation of
arterioles and capillaries (redness and warmth).
2. Increased vascular permeability. Loss of intravascular fluid and other blood components
results in stasis of blood flow and the accumulation of fluid (exudate) in the interstitial
tissues and/or body cavities. These account for swelling, pain and loss of function.
Note: Edema and/or effusion can be an exudate (due to an inflammatory process) or a
transudate (due to a non-inflammatory process). The pathogenesis of transudate will be
discussed in the sessions on hemodynamic disease processes. In the meantime, this table
summarizes the differences:
Etiology
Specific gravity (g/mL)
Total protein (g/dL)
Fluid/serum protein ratio
Fluid/serum LDH ratio
Fluid/serum glucose ratio
Cells (leukocytes)
TRANSUDATE
Increased hydrostatic pressure
<1.015
<3.0
<0.5
<0.6
>1.0
No
EXUDATE
Iinflammation
>1.015
>3.0
>0.5
>0.6
<1.0
Yes
Types of exudate vary with etiologic agent and site and degree of injury. The various types of
exudate will be discussed below.
3. Leukocytes accumulate at the site of injury in some types of inflammation. Neutrophils are
the predominant cell in and are characteristic of acute inflammation. The sequence of
events are as follows:
a. Margination (rolling). With loss of fluid and stasis circulating neutrophils accumulate
along the endothelial surface of capillaries and venules.
b. Adhesion. Neutrophils adhere to the endothelial surface. This involves specific
interaction between
1) adhesion molecules on the surface of the neutrophil. e.g. LFA-1 (CD11/CD18
integrins)
2) Adhesion molecules on neutrophils are enhanced by C5a
3) adhesion molecules on the surface of the endothelial cell e.g ICAM-1
(immunoglobulin family)
4) Adhesion molecules on endothelial cells are enhanced by IL-1 and TNF
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“Acute and Chronic Inflammation”
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The interaction between LFA-1 and ICAM-1 is frequently used as an example of
adhesion molecule interaction. For a full listing of such interactions (optional) see
Kumar, et al p. 38
c. Migration and chemotaxis. Adhered neutrophils next move between endothelial cells
to the site of injury. This is directed emigration and occurs in response to chemotactic
agents released at the site of injury. The chemotactic response is unidirectional and in
response to a chemical gradient.
The major chemotactic agents for neutrophils are
1)
2)
3)
4)
Bacterial products
Complement derivatives, e.g. C5a
Arachidonic acid derivates, e.g. leukotriene B4 (LTB4)
Cytokines – especially chemokines
d. Phagocytosis. If the injury is due to foreign particles (e.g. bacteria) the particles are
recognized by the neutrophil surface and adhere to it. Non-specific coating of such
particles by opsonins facilitates their phagocytosis. Opsonins include IgG and C3b in
blood. The foreign particle is enclosed by the cell membrane and ingested as a
membrane-bound structure, the phagosome. The bacterium is killed and lysed by:
1) Oxygen-dependent system. The ultimate step in the elimination of infectious agents
and necrotic cells is their killing and degradation within neutrophils and
macrophages, which occur most efficiently after activation of the phagocytes.
Microbial killing is accomplished largely by oxygen-dependent mechanisms.
Phagocytosis stimulates a burst in oxygen consumption, glycogenolysis, increased
glucose oxidation via the hexose-monophosphate shunt, and production of reactive
oxygen intermediates (ROIs, also called reactive oxygen sepecies). The generation
of reactive oxygen intermediates is due to the rapid activation of an oxidase (NADPH
oxidase), which oxidizes NADPH (reduced nicotinamide-adenine dinucleotide
phosphate) and, in the process, reduces oxygen to superoxide anion ( ). Superoxide
is then converted into hydrogen peroxide (H2O2), mostly by spontaneous
dismutation. Hydrogen peroxide can also be further reduced to the highly reactive
hydroxyl radical (OH). Most of the H2O2 is eventually broken down by catalase into
H2O and O2, and some is destroyed by the action of glutathione oxidase.
2) Oxygen-independent systems. These include lysozyme, lactoferrin and major basic
protein. Major basic protein is especially important in eosinophilic toxicity to
parasites.
3) Lysosomes. Phagosomes merge with neutrophilic lysomes to form phagolysosomes,
allowing activated enzymes to biodegrade the bacteria.
C. TYPES OF ACUTE INFLAMMATION. These are defined by the type of exudate which, in
turn, is determined by the etiologic agent, the site of injury and the severity of injury.
1. Serous Contains low MW proteins, especially albumin. Clear yellow fluid. No cells.
Examples: Blister in a second degree burn; Laryngeal edema in an acute anaphylactic
reaction to penicillin.
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2. Fibrinous Contains larger proteins, especially fibrin. Note: Make sure you distinguish
between the terms “fibrinous” and “fibrous”. Often coats a surface. No cells.
Examples: Fibrinous pneumonia (pneumonitis) in chlorine gas inhalation or viral infection,
e.g. influenza. Fibrinous pericarditis in rheumatic carditis.
3. Purulent (Suppurative) In addition to albumin, fibrin and other proteins, the exudate
contains neutrophils. A exudate composed of fluid, protein, and dead/dying neutrophils and
other cells is pus. Pyo- is the prefix which refers to pus.
Examples: Suppurative pneumonia or meningitis due to a pyogenic microorganism, e.g.
Neisseria meningitidis. Pyosalpinx – purulent infection of the fallopian tube e.g. due to
Neisseria gonorrhoeae.
4. Eosinophilic The eosinophil is prominent or predominant in this type of exudate. It
characteristically occurs in Type I hypersensitivity (allergic) reactions and certain
parasitic infections.
Examples: Asthma, allergic rhinitis; Nematode infection, ascariasis of small intestine.
5. Hemorrhagic Damage to endothelial cells and vessel walls allow RBCs to leak into the
surrounding tissue. Rickettsia are especially prone to damaged endothelial cells.
Example: Rocky Mountain Spotted Fever.
6. Mucinous Inflammation in tissue containing abundant mucin-secreting glands is likely to
stimulate secretion  mucus. Example: Bronchitis.
7. Pseudomembranous The injury results in necrosis of the affected tissue lining a surface.
This results in the formation of a “membrane” composed of fluid, proteins, neutrophils,
RBCs and necrotic tissue.
Example: Pseudomembrane obstructing the upper airway in diphtheria (Corynebacterium
diphtheriae); Pseudomembranous enterocolitis in patients treated with clindomycin and
develop intestinal infection due to Clostridium dificile.
* Many exudates are combined, e.g. fibrinopurulent or mucopurulent.
D. SPECIFIC TYPES
1. Abscess A focus of acute inflammation composed of pyogenic exudate and necrotic
tissue. Certain bacteria are especially likely to result in an abscess, e.g. Staphylococcus
aureus and Klebsiella pneumoniae. Although generally designated as “acute” an abscess
may be present for a long time. They may occur anywhere in the body and, in some
locations, may be present for a long time before diagnosis.
They may eventually become “walled off” by a fibrous connective tissue. They may be large
or microscopic and single or multiple. They may rupture into a hollow structure (e.g. a
ventricle in the brain) or drain (e.g. into a bronchus or the surface of the skin.
Furuncle (“boil”) – a subcutaneous abscess, usually arising in or near a hair follicle. S.
aureus is a common cause.
Carbuncle – coalesced furuncles.
2. Cellulitis A diffuse area of acute inflammation composed of edema fluid, bacteria and
neutrophils spread through tissue. Clinically characterized by a diffuse area of swelling,
redness, warmth and pain. Certain bacteria are especially likely to result in cellulitis, e.g.
Streptococcus pyogenes. Typically occurs in skin and subcutaneous tissues. Usually
necrosis is not present but, in certain instances, it may be a prominent feature, e.g. socalled flesh-eating infections.
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“Acute and Chronic Inflammation”
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3. Lymphangitis. Pyogenic infections may spread proximally via lymphatics; this may be
recognized clinically as red lines seen in the skin. Secondary involvement of draining lymph
nodes may result in acute lymphadenitis. The nodes are enlarged, soft (fluctuent) and
tender.
II. CHRONIC INFLAMMATION
In comparison with acute inflammation, chronic inflammation tends to be:
 Gradual in onset
 Of relatively lower intensity
 Longer lasting
The characteristic inflammatory cells are mononuclear cells, especially lymphocytes and/or
macrophages. Eosinophils and/or plasma cells may be present.
A. MACROPHAGES are derived mainly from monocytes in the circulating blood. They are
distinguished from “fixed macrophages” such as Kuppfer cells in the liver. Macrophages
are active in phagocytosis and produce a wide variety of biologically active products.
Fusion of macrophages results in giant cells (Langhans cells).
Tissue destruction is a hallmark of chronic inflammation.
Chronic inflammation may evolve from previous acute inflammation, but most often, it occurs de
novo in response to certain etiologic agents or with certain diseases. These include:
 Viral infections
 Certain bacterial infections, e.g. syphilis
 Autoimmune diseases, e.g. rheumatoid arthritis, chronic thyroiditis
 Transplant rejection
B. GRANULOMA reaction is a distinct type of chronic inflammation.
consisting of three types of cells.
It is a focal lesion
1. Epithelioid cells. Macrophages (CD68+) which morphologically resemble epithelial
cells.
2. Multinucleated (Langhans) giant cells.
Result from the coalescence of
macrophage/epithelioid cells.
3. Lymphocytes – Mostly CD4+ and some B cells (CD20+) and plasma cells form a
rim around the granuloma.
The pathogenesis of most granulomas is immune-mediated (Type IV hypersensitivity),
with activated CD4+ T-lymphocytes producing factors (especially gamma-interferon)
important in the transformation of CD68+ macrophages into epitheloid and giant cells.
Some granulomas, mainly those arising in response to inert foreign bodies, do not
appear to be immune-mediated.
Differential diagnosis:
1. Tuberculosis (caseating granuloma)
2. Atypical mycobacterial infections
3. Leprosy, cat-scratch disease, brucellosis, lymphogranuloma venereum
4. Fungal infections (especially when longstanding), e.g. histoplasmosis
5. Berylliosis
6. Foreign body
7. Sarcoidosis
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“Acute and Chronic Inflammation”
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C. SARCOIDOSIS: A disease of unknown etiology with presence of multiple non-caseating
granuloma formations (granulomata). Features include:
1. 90% of cases involve the hilar lymph nodes and lungs. Presentation may be as an
unexpected finding in a “routine” chest X-ray or a patient with low grade fever and
shortness of breath. Other non-specific findings include weight loss, fatigue, and
night sweats.
2. Since it can affect virtually any organ or organs in the body it may also present with
any of a large variety of clinical manifestations. Sarcoidosis has provided the New
England Journal of medicine (NEJM) with many Clinicopathological Conferences
(CPCs). It is one of those diseases which is part of almost any differential diagnosis.
3. The diagnosis depends on the demonstration of non-caseating granulomas, e.g. in a
bronchial biopsy, in a clinical context compatible with sarcoidosis. In the USA the
disease is endemic to the Middle Atlantic states, e.g. North Carolina, and is more
common in women and African-Americans.
4. Other sites of involvement include other lymph nodes, spleen, liver, bone marrow,
skin and salivary glands.
5. The granulomatous pattern suggests a persistent, poorly degradable antigen.
Various immunologic abnormalities are present and CD4+ T-lymphocytes play a
role.
6. In most cases the disease is indolent. In a small number of cases it is rapidly
progressive and in about 10% of cases the disease is the cause of death.
DEFICIENCIES IN THE INFLAMMATORY RESPONSE
These inflammatory deficiencies are analogous of the immunodeficiencies and result in
increased susceptibility to infection. Some are inherited and others are acquired. These include
the leukopenias (e.g. secondary to radiation therapy affecting bone marrow, defects in
leukocyte migration (e.g. in diabetes mellitus) and in phagocytosis (e.g. opsonin deficiency).
SPECIFIC DISEASES include:
1. Chediak-Higashi disease
a) Autosomal recessive
b) Infants and children
c) Neutropenia with recurrent infections
d) Oculocutaneous albinism
e) Aberrant granules in Neutrophils and other WBCs – “giant” lysosomes
f) Melanocytes – “giant” melanosomes
g) Basic defect is unknown – may be in microtubules
2. Chronic granulomatous disease of infancy
a) X-linked recessive in most cases, therefore usually in males
b) Infants and children
c) Recurrent infections, especially by catalase-producing microorganisms
d) A variety of histopathologic patterns is seen, especially granulomas
e) Basic defect is of NADPH oxidase – resulting in a deficiency of oxygen-dependent
generation of H202 and microbial killing.
3. Leukocyte Adhesion Deficiency, Type I
a) Inherited
b) Children
c) Recurrent infections, especially of mucosal surfaces and skin
d) Non-specific histopathology
e) Basic defect is of leukocyte integrins – beta2 subunit. LFA-1 is a beta2 integrin.
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“Acute and Chronic Inflammation”
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SYSTEMIC EFFECTS OF INFLAMMATION
Non-specific indicators of indicators of inflammation – laboratory tests:
1. “Left-Shift” -- A peripheral blood smear is examined and the percentage of each type of
WBC is determined. Some of the neutrophils may show immature types, e.g. “bands” – the
immediate precursors of mature neutrophils. The number/percentage of immature neutrophils is
increased in certain infections, notably bacterial infections. When the number of immature
neutrophils and, especially, if even less mature types are present in the peripheral smear – the
term leukemoid reaction is used.
2. Erythrocyte sedimentation rate (ESR) -- The rate at which RBCs “settle” to the bottom of a
tube is determined by the amount of protein in the blood. This, in turn, is largely determined by
the amount of fibrinogen. The amount of fibrinogen in the blood, and the erythrocyte
sedimentation rate (ESR), are increased non-specifically in patients who are undergoing an
inflammatory response.
3. C-reactive protein -- Blood levels of this glycoprotein are non-specifically elevated in
patients who are undergoing an inflammatory response. It is synthesized by the liver.
OTHER TOPICS:
- Erosion vs. Ulcer
Erosion: A focal defect limited to the epithelial lining or covering e.g. gastric mucosa or
epidermis.
Ulcer: A focal defect which extends beneath the epithelial lining e.g. to involve the
gastric submucosa or dermis.
- Fistula vs. sinus tract
Fistula: A communication between the lumina of hollow structures (e.g. an acquired
communication between two loops of bowel in Crohn’s disease or a congenital
malformation – tracheo-esophageal fistula. Fistulae may also communicate between a
hollow internal structure and the surface of the skin.
Sinus tract: Generally refers to a communication between subcutaneous tissue and the
surface of the skin, e.g. pilonidal sinus.
“Acute and Chronic Inflammation”
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Disease & Defense Block
TERMINOLOGY:
Abscess
Epithelioid cell
Macrophage
Acute phase reaction
Major basic protein
Adhesion molecules
ESR
Mast cell
Monocyte
Basophil
Fibrin (Fibrinous)
Fistula
Phagosome
Carbuncle
Furuncle
Phagolysosome
C-reactive protein
Pseudomembranous
C3b, C5a
Granuloma
Purulent
Cellulitis
Pyogenic
Chediak-Higashi disease
ICAM-1
Chemotaxis
Integrins
Selectins
Serous
Langhans giant cell
Sinus tract
Cytokines
Leukemoid reaction
Suppurative
Leukocyte adhesion deficiency
Edema
Transudate
Effusion
LFA-1
Erosion
Lymphadenitis
Ulcer
Exudate
Lymphangitis
Eosinophil
Lysosom
Chronic granulomatous disease
Disclaimers:
1. The primary goal of this chapter is to study the learning objectives outlined at the beginning
of this handout. The material to study is provided in the lectures, the handouts and the
recommended textbooks. All these sources provide the content over which you will be tested.
The lectures are intended to provide broad information of the material found in the textbooks
and handouts, and to give the students the opportunity to ask questions on subjects not clear
in the texts. The handouts do not seek to follow up the sequence of the lectures, and most
importantly, they are not a surrogate of the books.
2. The text presented in this handout has been edited by Dr. La Rosa from material found in
your books, from published articles and other educational works. This handout is solely for
educational purpose and not intended for commercial or pecuniary benefit (see USA
Copyright Law, Section 110, “Limitations on exclusive rights: Exemption of certain
performances and displays”). Reproduction and use of this handout can be done only for
educational use.
[Download] the USA Copyright Law version, October 2009.