MOD #17
Fri 04/25/03 11am
Dr. Wasson
M. Shiller
Proscribe Samera Kasim
Page 1 of 12
Introduction to Acute and Chronic Inflamation
I. What to study
a. You are responsible for pages 50-87 of Robbins textbook
b. Review the learning objectives on the Interactive Case Study Companion
to Robbins Pathologic Basis of Disease; CD-ROM
c. Know the scenarios and cases (titled Inflammation and Repair), on the
above CD-ROM (this applies to both chapters 3 and 4) (Cases 1 – 5)
i. Concentrate on inflammation cases (repair will be next)
ii. CD ROM is on the INTRAnet off the courses web page or at
Majors.
II. Course Objectives:
a. Organize “pathologic/clinical” thinking by asking the following questions
b. What is the common or pathognomonic clinical presentation?
c. What is/are the salient pathogenic mechanism(s)?
d. Salient histomorphology? (don’t need to know specific detail, just general)
e. What is/are molecular biologic features that are currently known?
f. Clinical course? (i.e., biologic activity)
g. Treatment? (will touch on briefly)
h. Other noteworthy features
III. DFN: inflammation
a. “what characterizes the inflammatory process in higher forms is the
reaction of blood vessels, leading to the accumulation of fluid and
leukocytes (WBC) in extravascular tissues. The inflammatory process is
closely intertwined with the process of repair – and (both) are
fundamentally protective responses. However (both) may be potentially
harmful (and cause injury).”
IV. Figure: inflammatory response components
a. Vessels with platelets and WBC
b. Endothelial cells which form the vessels
c. Extracellular CT tissue matrix and the cells in the matrix
i. All of these work together to elicit the inflammatory response
V. Figure: acute inflammation
a. Involves both cellular and vascular elements
i. Cellular elements includes 4 steps
1. extravasation (which has 4 steps, see below)
2. chemotaxis
3. leukocyte activation
4. phagocytosis
b. Vasodilation leads to increased blood flow and incr fluid leakage in the
extracellular tissue matrix
i. This is what causes heat, redness and edema
c. Know the mediators and receptors for the inflam process.
d. Know the hypothesis of how it occurs
MOD #17
Fri 04/25/03 11am
Dr. Wasson
M. Shiller
Proscribe Samera Kasim
Page 2 of 12
VI. Figure: extravasation
a. Consists of 4 steps:
i. Rolling
ii. Activation
iii. Adhesion
iv. Transmigration
v. Receptors are important in the inflammatory process and include:
1. Selectins
2. integrins
3. immunoglobulins (Ig)
vi. the bars on the figure map out where and when these receptors are
imporant
vii. know their purpose: how and where they interact in the
process
1. know which ones are on the surface of the leukocytes
2. know which are on the surface of the endothelium and how
they interact
3. PECAM receptor is important in extravastion
VII. Figure: chemotaxis (EM of leukocyte)
a. Psuedopods from the WBC move toward an agent and the body follows
b. This is accomplished by an actin/myosin complex
VIII. Leukocyte Activation
a. Know the key biochemical events in leukocyte activation
IX. Figure: phagocytosis
a. Know the events of phagocytosis
i. Recognition
ii. Attachment
iii. Engulfment
iv. Formation of the phagosome (where killing/degradation occurs)
b. know about opsonization which occurs during recognition
i. know the major opsonins
c. There are 2 ways that degradation can be accomplished
i. Oxygen dependent mechanism
1. the primary pathway
2. uses NADPH oxidase reaction
3. know this reaction: the reactants, enzymes, products
and byproducts
a. leads to superoxide and hydrogen peroxide
b. hydrogen peroxide interacts with myeloperoxidase
to create a bactericidal agent
ii. Oxygen independent mechanism
1. formation of the hydroxide radical is a secondary
mechanism of phagocytosis
d. Degradation products are released to the outside
i. The products are what attract leukocytes and cause injury
MOD #17
Fri 04/25/03 11am
Dr. Wasson
M. Shiller
Proscribe Samera Kasim
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X. Table 3-2, page 64 Clinical examples of leukocyte-induced injury
a. Ie. Injuries that occur as a result of leukocyte going to an area where
degradation products have been released from the lysosome
i. “during chemotaxis and phagocytosis, activated leukocytes may
release toxic metabolites and proteases extracellularly, potentially
causing tissue damage.” robbins, p65
b. acute
i. ARDS (acute respiratory distress syndrome)
ii. Acute transplant rejection
iii. Asthma
iv. Glomerulonephritis
v. Reperfusion injury
vi. Septic shock
vii. Vasculitis
c. chronic
i. Arthritis
ii. Asthma
iii. Atherosclerosis
iv. Chronic lung disease
v. Chronic (transplant) rejection
vi. Others
d. Asthma and transplant rejection have both an acute and chronic
component
XI. Defects of leukocyte function
a. Generally result in recurrent bacterial infections
b. Genetic –
i. CGD (chronic granulomatous disease)
1. associated with recurrent infection
2. from a NADH oxidase deficiency
a. reduced ability to use the oxygen dependent method
of killing bacteria, which is the primary mechanism
used
b. results in decr ability to kill bacteria (phagocytosis)
c. these patients don’t actually get granulomas, which
are discussed below
ii. Chediak-Higashi Syndrome
a. associated with recurrent infection, albinism,
bleeding disorders
b. There are degrative problems in the lysosomes,
which cause the recurrent infection
c. There are also problems with degradation in the
Melanocytes = albinism
d. Defective degradation in the platelets lead to
bleeding disorders
c. acquired (much more common)
MOD #17
Fri 04/25/03 11am
Dr. Wasson
M. Shiller
Proscribe Samera Kasim
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i. Diabetes mellitus
ii. Malignancy
iii. Immunodeficiency states of all types
1. EX: HIV
iv. The very young and the elderly
1. both are considered immuno-compromised
XII. Fig: Acute and Chronic inflammation timeline
a. Histo slide on left is acute, right is chronic
b. Graph shows a timeline of inflam
c. Edema occurs in the first couple hours from interstitial fluid buildup
i. These look like clear spaces between cells in the microscope (as do
all fluid filled spaces)
d. Infiltration of acute inflammatory cells occurs within 24 hours
i. Include neutrophils
e. At ~42-78 hours, monocytes and macrophages may begin to appear,
which is indicative of the chronic inflamm phase
i. The slide on the right shows muscles cells, but notice the large
space where there are mononuclear cells, including leukocytes,
plasma cells and macrophages
ii. Phase is marked by macrophages which stimulate fibrosis, or the
healing process
iii. fibrosis replaces the myocytes (seen as pink background on the
slide)
f. At 2-3 days (42-78 hours) you’ll see chronic inflamm cells indicating
entry into the early stages of chronic inflam, but there are still more acute
inflam cells. True chronic inflam normally occurs after 1-2 weeks.
XIII. Fig: chemical mediators of inflam
a. There are MANY of these; concentrate on those highlighted in lecture and
in the book
b. 2 categories:
i. secreted from the cell
1. can either be preformed in the cell or synthsized
2. 2 Most imp preformed mediators are the vasoactive
amines: histamine and serotonin
3. Know their source
a. Mast cells
b. Basophils
c. Platelets
4. know what triggers their release
5. know what their effects are
ii. Found in the Plasma
1. most come from the liver
2. includes plasma proteases
3. generated from 4 different pathways
XIV. fig: Omentum slide
MOD #17
Fri 04/25/03 11am
Dr. Wasson
M. Shiller
Proscribe Samera Kasim
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a.
b.
c.
d.
e.
fig 3-15, p66
predominantly a fatty tissue
stained with fat stain and metachromatic stain
fat = red stain
deep purple = granules of mast cells which release histamine when
stimulated
i. each of the deep purple condensations are packed full of granules.
ii. Would see better at higher mag
XV. Fig: inflammatory complement mediators
a. Shows an overveiw of complement activation pathway which is the
convergence of 2 pathways, the classic and alternative pathways.
b. Activation of the pathways creates
i. potent inflam mediators: C3a, C5a
ii. A membrane attack complex (MAC)
XVI. Fig: Interrelationship of 4 plasma mediator systems
a. Be able to define the role of each
b. Know that although we learn them all separately, one cascade effects the
next
c. We will focus mainly on the kinin and complement cascade for acute
inflame
d. BUT! Be able to recognize the clotting and fibrinolytic cascades and the
role they play in the complement cascade
i. We’ll hit on these more when we get to thrombosis
ii. Factor XII, Hageman factor, activates both the kinin and
clotting cascade
iii. The kinin cascade generates bradykinin, a potent chemical
mediator you need to know
1. bradykinin come from High Molecular Weight kininogen
(HMWK)
2. again, know C3a, C5a, and MAC
XVII. Inflam eicosanoids
a. Other mediators stem from Arachidonic acid (AA)
b. Arachidonic acid is from Phospholipids of the cell membrane, released by
phospholipase
c. AA is then acted upon by lipoxygenase and cyclooxygenase to form
i. Leukotrienes
ii. Prostaglandins
iii. Thromboxane
d. Know which mediators come through which enzyme system and their
effects
e. Steriods inhibit phospholipase, which is an enzyme above AA, thus are
potent anti-inflam agents
f. Aspirin and indomethicin inhibit the action of cyclooxygenase
MOD #17
Fri 04/25/03 11am
Dr. Wasson
M. Shiller
Proscribe Samera Kasim
Page 6 of 12
XVIII.
XIX.
XX.
XXI.
XXII.
XXIII.
i. These are non-steroidal anti-inflam that decrease the production of
mediators, decr vaso dialation, decrease platelet aggregation, and
thus decrease edema, heat, swelling and fever
Fig: Chemokines
a. Another grp of chemical mediators are chemokines, or cytokines
b. Examples are IL-1/TNF (Interluekin 1 and tumor necrosis factor)
i. Come from macrophages
c. 4 effects
i. acute phase reactions
ii. endothelial effects
iii. fibroblast effects
iv. leukocyte effects
1. increase cytokine secretion and propagation of the inflam
response
Fig: Nitric Oxide
a. Know action and role
b. There are 3 forms
i. Endothelial
ii. Nueronal
iii. Inducer
1. first two are activated similarly
2. only the endothelial and inducer type are on the figure
Fig: Chemical mediators from macrophages and nuetrophil granules
a. Only know the important ones
i. Lysozyme
ii. Myeloperoxidase
1. enzyme in oxygen dependent killing mechanism in
degradation
iii. don’t need to know the whole list
Summary of acute mediators
a. Know Table 3-6, p. 77
i. The actions in the chart are not complete and you should read the
text to get the rest of it
Outcomes of acute inflammation
a. chronic inflammation
i. Paradoxically, can be one of the outcomes of acute inflammation
b. Resolution
i. Acute inflam can resolve; take a biopsy of an area where inflam
occurred and you cannot detect that inflammation was there
c. Abscesses
i. Will discuss later
d. Regeneration/scarring
e. Chronic inflammation can also occur directly from injury or mediators
(persistent infection, toxins, etc)
Chronic inflammation
MOD #17
Fri 04/25/03 11am
Dr. Wasson
M. Shiller
Proscribe Samera Kasim
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a. Definition
i. prolonged duration (weeks or months) of active inflammation,
tissue destruction, and attempts at repair are proceeding
simultaneously.
b. Causes
i. Persistent infections
ii. Prolonged exposures to potentially toxic agents (exogenous or
endogenous)
1. EX: silicosis and atherosclerosis
a. Silicosis Inflam and fibrosing in lungs
iii. Autoimmunity
1. EX: rheumatoid arthritis
2. autoimmune hepatitis - involves chronic inflam of organs
involved in tissue destruction and fibrosis
c. histologic features
i. Mononuclear cells
1. including lymphocytes, plasma cells, and macrophages
ii. Tissue destruction
1. as in previous figure where the myocytes had been
destroyed (timeline figure)
iii. Healing
1. angiogenesis (new vessel formation)
2. fibrosis
iv. because of the definition of chronic inflammation, you MUST
see these 3 things
XXIV. fig: histo slide of lung
a. this lung has chronic inflam, so MUST have all 3 components
b. see page 80 in book. There is a good legend under the figure
c. from left to right on the slide, you see:
d. residual alveolus (tissue destruction)
i. alveolar lining cells have transformed from simple squamous to the
more “repairative” cuboidal epi.
e. There is a thickened septa from deposition of collagen = fibrosis
i. usually these are delicate so that air exchange can occur
f. Dark condensed circle: mononuclear cells; there is accumulation of
lymphocytes, marcophages and plasma cells
XXV. Mononuclear infiltration: Cells and Mechanisms
a. macrophages (very important cell in chronic inflammation, but only
one component of the mononuclear phagocyte system)
i. Maturation
ii. Continued recruitment from circulation
iii. Local proliferation
iv. Immobilization (in certain cases)
XXVI. Fig: maturation of monocuclear phagocytes
a. Originate from stem cells in the bone marrow
MOD #17
Fri 04/25/03 11am
Dr. Wasson
M. Shiller
Proscribe Samera Kasim
Page 8 of 12
b. Then Differentiate into a monoblast.
c. Once a monoblast is made, then a macrophage must form
i. Stem cell  monoblast  monocyte  macrophage
d. Monoblasts are found in the blood
e. They migrate to the tissue and after extravasation it becomes a
macrophage
f. The macrophage can become activated and turn into epithelial-like cells or
clump together to form giant cells (which produce chemical mediators)--more on this stuff later….
g. Macrophages can migrate to specific locations and become specialized
cells:
i. In the liver, they’re Kupffer cells
ii. In the lungs, they’re alveolar macrophages
h. Remember that stem cells can differentiate int granulocytes, erythroblasts,
or monoblasts etc….
XXVII. Fig: macrophage activation
a. 2 stimuli activate macrophages:
i. immune
1. from activated T cells which secrete interferon gamma,
which activate macrophage secretion of mediators
ii. non-immune
1. from endotoxin, fibronectin and other chemical mediators
iii. activated macrophages secrete mediators that can cause tissue
injury, fibrosis, and inflammation (the triad for chronic
inflammation)
XXVIII. Table 3-9, pg 81
a. Don’t need to know all the compounds. Know those that “seem
important” (hmmmmm……)
i. Ie. Mentioned in lecture, multiple times in text, etc
ii. Ex: IL-I, TNF
iii. Some will be covered in future chapters/lectures
b. Again, The macrophage is a central figure in chronic inflammation –
activated macrophages produce a great number of biologically active
compounds
XXIX. other important cellular elements in chronic inflammation
a. Lymphocytes
b. T cells
c. B cells: plasma cell
i. Plasma cells are activated B cells
d. Mast cells (IgE)
e. Eosinophils
i. Seen withAllergies, parasitic infestations, and asthma
f. [neutrophils]
i. some might be present in chronic inflam, but not a key factor
ii. this is normally an acute inflam cell
MOD #17
Fri 04/25/03 11am
Dr. Wasson
M. Shiller
Proscribe Samera Kasim
Page 9 of 12
XXX. fig: histo slide of chronic inflam
a. can see epitheliod type macrophages, aka histiocytes, which (stain light)
b. eosinophils have bright orange granules
c. a few plasma cells are present (have dark staining nucleus)
XXXI. granulomatous inflammation**
a. See Table 3 – 9, pg. 83**
b. This is a type of chronic inflammation with distinct patterns
c. Definition of a granuloma
i. Epithelioid cells
ii. Giant cells
1. this is a fusion of macrophages
d. Types of granulomas
i. Foreign body
1. ex: suture material that gets into a wound and is engulfed
by the macrophage. Can often see the engulfed material
inside the granuloma
ii. immune
e. Examples of granulomatous inflammation**
i. Tuberculosis
1. this is an example of the immune type of granuloma
wherein there is an Antibody-antigen reaction
ii. Leprosy
iii. Syphilis
1. etiology: Trepnonema pallidum
2. a loose granulomatis inflam; not a classic ex.
iv. Cat-scratch disease
1. a necratising granuloma characterized by the accumulation
of neutrophils
2. will see classic epitheliod histiocytes and giant cells
3. thus these granulomas look different
v. Other causes
1. ex: sarcoidosis whose etiology is unknown
XXXII. fig: histo slide of granulomatas inflam
a. Clearing just the left of mid-slide:
i. Kazius necrosis – necrotic material where the outline of cells in
indistinct
ii. Seen in TB, leprosy and fungal infection (histoplasmosis)
iii. Necosis is NOT seen in sarcoidosis
b. Bottom, right of midline
i. Giant cells
1. nuclei around the edge
2. specific for TB
ii. bottom right corner
1. chronic inflam cells
XXXIII. lymphatics
MOD #17
Fri 04/25/03 11am
Dr. Wasson
M. Shiller
Proscribe Samera Kasim
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XXXIV.
XXXV.
XXXVI.
XXXVII.
XXXVIII.
a. together with lymph nodes, filter and police the extravascular
fluids:function with the mononuclear phagocyte system
b. know histomorphology (see paragraph in robbins describing how they’re
different from arteries/veins)
c. lymphatic inflammation (as occurs in lymphadenitis)
d. bacteremia (essentially, pathogens have defeated the lymphatic system);
the next line of defense is the reticuloendothelial system: liver, spleen,
bone marrow
i. the lymphatic system can spread infection
morphologic patterns in acute and chronic inflammation**
a. under the microscope, seen as:
b. serous (feature: effusion)
i. typically a transudate
ii. low protein concentration
iii. few inflam cells, such as lymphocytes
iv. as seen in pleuralitis or ascites
c. fibrinous
i. exudate
ii. high [protein] and [neutraphils]
iii. ex: pericarditis
iv. fibrinous can etiher resolve or organize (as in fibrosis)
d. suppurative/purulent
i. pyogenic organisms (ex Staphylococcus aureus)
ii. abscess formation (which are the accumulation of neutrophiles
with central necrosis)
e. ulcers (sloughing of inflammatory/necrotic tissue of epithelium)
fig: histo slide
a. top to bottom
b. keratin
c. epithelium
d. inflam cells are present such as lymphocytes
e. subepidermal blister (bula); clear because fluid filled
fig: hist slide
a. P = pericardium
b. F = fibrinous exudate
c. Shows hemorrhage and inflammation
d. Contains predominately fibrin and contains trapped RBCs
e. A RBC is seen just to the right of the “F”
Fig: Microabscess in the myocardium
a. Aggregate of neutrophils
b. Center of slide = coagulative necrosis
c. Also contains necrotic debri
d. Larger absesses of the lung and brain can be depicted on CT’s (3-5 cm)
Fig: ulcer of duodenal mucosa
a. Glandular epithelium
MOD #17
Fri 04/25/03 11am
Dr. Wasson
M. Shiller
Proscribe Samera Kasim
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b. Can also see same thing in stomach, colon and skin
c. Note ulcer edge, base
d. At the base there’s a fibrous exudate and inflammation
XXXIX. Systemic Effects Of Inflammation
a. Usually caused by chemical mediators
b. Fever
i. (prominent manifestation): coordinated by the hypothalamus; a
complex orchestration of endocrine, autonomic and behavioral
responses
ii. IL-1, IL-6 TNF, and Prostaglandins are key to fever
1. thus certain anti-inflam reduce fever as discussed above.
iii. A malignancy, such as in Hodgkins lymphoma can cause fever
because these mediators are over produced
c. Leukocytosis (prominent manifestations)
i. This is an elevated WBC count
ii. (>10,000 cells)
iii. Leukamoid reactions
1. “shift to the left” = bands, metacytes and myelocytes are
present (ie. Immature cells)
2. important because can be present at 10,000 WBC count or
at 40,000. This changes your differential from leukemia to
neoplasia, for example
iv. Neutrophilia
v. Lymphocytosis
vi. Eosinophilia
1. seen in allergic reactins, asthma
d. Leukopenia
i. 90% of cells = lymphocytes, thus there are few neutrophils left
(neutropenia)
ii. prone to a secondary acute infection
iii. high activated leukocytes are typical in response to viruses
(infectous mononucleosis)
XL. Study tipsa. acute/chronic inflammation, Interactive cases
b. Concentrate upon major entities
c. Especially note the figures, tables, bolded or italicized items – these either
tend to summarize or are considered important enough to emphasize
d. Be able to understand and apply unifying concepts, i.e. “The general
features of inflammation”: “Overview of the Inflammatory Response ”
e. Be able to define the major entities, headings
f. My powerpoint slides (use as a guide)
g. Know the “most commons” or those entities typically associated with a
disorder or major function
h. Know the Interactive Cases
MOD #17
Fri 04/25/03 11am
Dr. Wasson
M. Shiller
Proscribe Samera Kasim
Page 12 of 12
NOTE: In a properly-functioning immune system, healing begins almost as soon as
inflammation begins