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72 Cards in this Set

  • Front
  • Back
Define acute inflammation
1. Transient and early response to injury
2. Involves release of chemical mediators
3. Leads to stereotypic vessel and leukocyte responses
4. Not a synonym for infection
Describe the cardinal signs of acute inflammation
1. Rubor and calor
-Histamine-mediated vasodilation of arterioles
2. Tumor (swelling)
a. Histamine-mediated increase in permeability of venules
b. Synonymous with edema
-Increased fluid in the interstitial space
3. Dolor (pain)
-Prostaglandin (PG) E2 sensitizes specialized nerve endings to the effects of bradykinin and other pain mediators
4. Functio laesa (loss of function
Describe the stimuli for acute inflammation
1. Infections (eg, bacterial or viral infection)
2. Immune reactions (eg, reaction to a bee sting)
3. Other stimuli
-Tissue necrosis (eg acute myocardial infarction), trauma, radiation, burns, foreign body (eg, glass, splinter)
Describe the sequential vascular events of acute inflammation
1. Vasoconstriction of arterioles
-Neurogenic reflex that lasts only seconds
2. Vasodilation of arterioles
a. Histamine and other vasodilators (eg NO) relax vascular smooth muscle, causing increased blood flow
b. Increased blood flow increases hydrostatic pressure
3. Increased permeability of venules
a. Histamine and other mediators contract endothelial cells producing endothelial gaps
-Tight junctions are simpler in venules than arterioles
b. A transudate (protein and cell-poor fluid) moves into the interstitial tissue
4. Swelling of tissue (tumor, edema)
-Net outflow of fluid surpasses lymphatic ability to remove fluid
5. Reduced flood flow
-Decrease n hydrostatic pressure caused by outflow of fluid into the interstitial tissue
Describe the sequential cellular events of acute inflammation
-These events describe will emphasize neutrophil events in acute inflammation due to a bacterial infection (S. aureus)
1. Neutrophils are the primary leukocytes in acute inflammation
2. Margination
3. Rolling
4. Adhesion
Describe margination
1. RBCs aggregate into rouleaux ("stack of coins") in venules
2. Neutrophils are pushed from the central axial column to the periphery (margination)
Describe rolling
1. Due to activation of selectin adhesion molecules on the surface of neutrophils and endothelial cells
2. Neutrophils loosely bind to selectins and "roll" along the endothelium
Describe the adhesion molecules that firmly bind neutrophils to endothelial cells
1. neutrophils in the peripheral blood are subdivided into a circulating pool and a marginating pool (already attached to endothelial cells)
2. Normally, ~50% of peripheral blood neutrophils are in the circulating pool and ~50% in the marginating pool
3. This distribution can be altered by activating or inactivating neutrophil adhesion molecules
Describe the neutrophil adhesion molecules
1. B2-integrins (CD11a:CD18)
2. Adhesion molecule activation is mediated by C5a and leukotriene B4 (LTB4)
3. Catecholamines, corticosteroids, and lithium inhibit activation of adhesion molecules
a. Peripheral blood neutrophil count (neutrophilic leukocytosis) is increased
b. Normal marginating pool is now part of the circulating pool
Describe how endotoxins enhance activation of adhesion molecules
1. Peripheral blood neutrophil count (neutropenia) is decreased
2. Normal circulating pool is now part of the marginating pool
Describe endothelial cell adhesion molecules
1. Intercellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM) bind to integrins on the surface of neutrophils
2. ICAM and VCAM activation is mediated by interleukin 1 (IL-1) and TNF
Describe Leukocyte adhesion deficiency (LAD)
1. Autosomal recessive disorder
2. LAD type 1 is a deficiency of CD11a:CD18
3. LAD type 2 is a deficiency of a selectin that binds neutrophils
4. Clinical findings
a. Delayed separation of the umbilical cord (~1 month)
-Neutrophil enzymes are important in cord separation
b. Severe gingivitis, poor wound healing, peripheral blood neutrophilic leukocytosis (loss of marginating pool)
Describe transmigration (diapedesis)
1. Neutrophils dissolve the basement membrane and enter interstitial tissue
2. Fluid rich in proteins and cells (ie exudate) accumulates in interstitial tissue
3. Functions of exudate
a. Dilutes bacterial toxins
b. Provides opsonins (IgG, C3b) to assist in phagocytosis
Describe chemotaxis
1. Neutrophils follow chemical gradients that lead to the infection site
2. Chemotactic mediators bind to neutrophil receptors
-Mediators include C5a, LTB4, bacterial products, and IL8
3. Binding causes the release of Ca, which increases neutrophil motility
Describe phagocytosis
-Multistep process, consisting of three steps
1. Opsonization
2. Ingestion
3. Killing
Describe Opsonization
1. Opsonins attach to bacterial (or foreign bodies)
a. Opsonins include IgG, C3b fragment of complement, and other proteins (eg C-reactive protein)
b. Neutrophils have membrane receptors for IgG and C3b
2. Opsonization enhances neutrophil recognition and attachment to bacteria
3. Bruton's agammaglobulinemia is an opsonization defect
Describe Ingestion
1. Neutrophils engulf (phagocytose) and then trap bacteria in phagocytic vacuoles
2. Primary lysosomes empty hydrolytic enzumes into phagocytic vacuoles producing phagolysosomes
-In Chediak-Higashi syndrome, a defect in microtubule function prevents phagolysosome formation
Describe the O2-dependent myeloperoxidase (MPO) system of bacterial killing
1. Only present in neutrophils and monocytes (not macrophages)
2. Production of superoxide free radicals
-Reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase converts molecule O2 to O2*, which releases energy called to respiratory, or oxidative, burst
3. Production of peroxide (H2O2)
-Superoxide dismutase converts O2* to H2O2, which is neutralized by glutathione peroxidase
4. Some peroxide is converted to hydroxl free radicals by iron
5. Production of bleach (HOCl*)
-MPO combines H2O2 with chloride (Cl-) to form hypochlorous free radical (HOCl*), which kill bacteria
6. Chronic granulomatous disease and MPO deficiency are examples of diseases that have a defect in the O2-dependent MPO system
7. Deficiency of NADPH (eg glucose-6-phosphate dehydrogenase deficiency) produces a microbicidal defect
Describe the O2-independent myeloperoxidase (MPO) system of bacterial killing
1. Refers to bacterial killing from substances located in leukocyte granules
2. Examples: Lactoferrin (binds to iron necessary for bacterial reproduction) and major basic protein (eosinophil product that is cytotoxic to helminths)
Describe the chemical mediators of acute inflammation
1. They derive from plasma, leukocytes, local tissue, bacterial products
-Example: Arachidonic acid mediators are released from membrane phospholipids in macrophages, endothelial cells, and platelets
2. They have short halflives
3. They may have local and systemic effects
-Example: Histamine may produce local signs of itching or systemic signs of anaphylaxis
Describe the diverse functions of chemical mediators of acute inflammation
1. Vasodilation
-Examples: Histamine, NO, PGI2
2. Vasoconstriction
-Examples: Thromboxane A2 (TXA2)
3. Increase vessel permeability
-Examples: Histamine, bradykinin, LTC4-D4-E4, C3a and C5a (anaphylatoxins)
4. Produce Pain
-Examples- PGE2, bradykinin
5. Produce fever
-Examples- PGE2, IL1, TNF
6. Chemotactic
-Examples- C5a, LTB4, IL8
Describe the types of acute inflammation
Location, cause, and duration of inflammation determine the morphology of an inflammatory reaction
Describe purulent (suppurative) inflammation
1. Localized proliferation of pus-forming organisms, such as S. aureus (eg skin abscess)
2. S. aureus contains coagulase, which cleaves fibrinogen into fibrin and traps bacteria and neutrophils
Describe Fibrinous inflammation
1. Due to increased vessel permeability, with deposition of fibrin-rich exudate
2. Often occurs on the serosal lining of the pericardium, peritoneum, or pleura
-Dance of adhesions
3. Example- fibrinous pericarditis
Describe chronic granulomatous disease (CGD)
-X-linked recessive disorder (65%) or autosomal recessive disorder (35%)
-X-linked type characterized by deficiency NADPH oxidase in the cell membranes of neutrophils and monocytes
-The reduced production of O2* results in an absent respiratory burst
-Granulomatous inflammation occurs in tissue, becasue the neutrophils, which can phagocytose bacteria but not kill most of them, are eventually replaced by cells associated with chronic inflammation, mainly lymphocytes and macrophages.
-Macrophages fuse together to form multinucleated giant cells
-Patients have severe infections involving lungs, skin, visceral organs, and bones
Describe the test and treatment for Chronic granulomatous disease
-The classic screening test for CGD is the nitroblue tetrazolium test
-In this test, leukocytes are incubated with the colorless NBT dye, which is converted to a blue color if the respiratory burst is intact
-This test has been replaced by a more sensitive test involving oxidation of dihydrorhodamine to fluorescent rhodamine
-Bone marrow transplantation is a treatment of choice for the XR type of CGD
Describe what happens to bacteria in a patient with chronic granulomatous disease
-Catalase positive organisms that produce H2O2 are ingested by not killed because the catalase degrades H2O2
-Myeloperoxidase is present, but HOCl- is not synthesized because of the absence of H2O2
-Catalase negative organisms are ingested and killed when myeloperoxidsase combines H2O2 with Cl to form HOCl*
-Granulomatous inflammation occurs in tissue, becasue the neutrophils, which can phagocytose bacteria but not kill most of them, are eventually replaced by cells associated with chronic inflammation, mainly lymphocytes and macrophages.
Describe myeloperoxidase (MPO) deficiency
-Autosomal recessive disorder
-Differs from CGD in that both O2* and H2O2 are produces (normal respiratory burst)
-However, the absence of MPO prevents synthesis of HOCL*
Describe the sources and functions of prostaglandins
Sources:
Macrophages, endothelial cells, platelets
PGH2: Major precursor of PGs and thromboxanes

Functions:
PGE2: Vasodilation, pain, fever
PGI2: Vasodilation, inhibition of platelet aggregration
Describe the sources and function of Thromboxane A2
Sources:
Platelets, Converted from PHG2 by thromboxane synthase

Function:
Vasoconstriction, platelet aggregation
Describe the sources of Leukotrienes
Leukocytes, Converted from arachidonic acid by lipoxygenase-mediated hydroxylation
Describe the function of LTB4
Chemotaxis and activation of neutrophil adhesion molecules
Describe the function of LTC4, LTD4, LTE4
Vasoconstriction, increased venular permeability, bronchoconstriction
Describe the function of Zileuton
Inhibits 5-lipoxygenase: decreases synthesis of LTB4, LTC4, LTD4, and LTE4
Describe the function of Montelukast leukotriene receptor antagonist
Decreases synthesis of LTC4, LTD4, LTE4
Describe the source and function of bradykinin
Source:
Product of kinin system activation by activated factor XII

Functions: Vasodilation, increased venular permeability, pain
Describe the source and function of chemokines
Source:
Leukocytes, endothelial cells

Functions:
Activate neutrophil chemotaxis
Describe the source and function of complement
Source: Synthesized in liver (acute phase reactant)

Function:
-C3a, C5a (anaphylatoxins): stimulate mast cell release of histamine
-C3b: opsonization
-C5a: activation of neutrophil adhesion molecules, chemotaxis
-C5-C9 (membrane attack complex): cell lysis
Describe the source and function of IL1, TNF
Source:
Macrophages (main), monocytes, dendritic cells, endothelial cells

Function
-Initiate PGE2 synthesis in anterior hypothalamus, leading to production of fever
-Activate endothelial cell adhesion molecules
-Increase liver synthesis of acute-phase reactants, such as ferritin, coagulation factors (eg fibrinogen) and C-reactive protein
-Increase release of neutrophils from bone marrow (neutrophil leukocytosis)
-TNF is a promoter of apoptosis
Describe the function of IL-6
Increase liver synthesis of acute phase reactants
Describe the function of IL-8
Chemotaxis
Describe the source and function of histamine
Source: Mast cells (primary cell), platelets, enterochromaffin cells

Functions: Vasodilation, increased venular permeability
Describe the source and function of Nitric Oxide (NO)
Source: Macrophages, endothelial cells, Free radical gas released during conversion of arginine to citrulline by NO synthase

Functions: Vasodilation, bactericidal
Describe the source and function of serotonin
Source: Platelets

Function: Vasodilation, increased venular permeability, increased collagen synthesis
Describe serous inflammation
1. Thin, watery exudate
-Insufficient amount of fibrinogen to produce fibrin
2. Examples: blister in second-degree burns, viral pleuritis
Describe pseudomembranous inflammation
1. Bacterial toxin-induced damage of the mucosal lining, producing a shaggy membrane composed of necrotic tissue
2. Example: Pseudomembranous associated with Clostridirum difficile in pseudomembranous colitis
-Corynebacterium diphtheriae produces a toxin causing pseudomembrane formation in the pharynx and trachea
Describe the role of fever in acute inflammation
1. Right shifts oxygen binding curve
-More O2 is available for the O2 dependent MPO system
2. Provides a hostile environment for bacterial and viral reproduction
Describe the factors involves in the termination of acute inflammation
1. Short half-life of inflammatory mediators
2. Lipoxins
3. Resolvins
4. Clearance of neutrophils by apoptosis
Describe Lipoxins
1. Anti-inflammatory mediators
2. Derive from arachidonic acid metabolites (eg LXA4, LXB4)
3. Inhibit transmigration and chemotaxis
4. Signal macrophages to phagocytose apoptotic bodies
Describe Resolvins
1. Synthesized from omega-3 fatty acids
2. Inhibit production and recruitment of inflammatory cells to the site of inflammation
Describe the possible consequences of acute inflammation
1. Complete resolution
a.Occurs with mild injury to cells that have the capacity to enter the cell cycle (eg labile and stable cells)
2. Tissue destruction and scar formation
-Occurs with extensive injury or damage to permanent cells
3. Formation of abscesses
4. Progression to chronic inflammation
Define chronic inflammation
Inflammation of prolonged duration (weeks to years) that most often results from persistence of an injury-causing agent
Describe the causes of chronic inflammation
1. Infection
-TB, leprosy, hep C
2. Autoimmune disease
-Rheumatoid arthritis, Systemic Lupus erythematoss
3. Sterile agents
-Silica, Uric acid, Silicone in breast implants
Describe the Cell types involved in chronic inflammation
Monocytes and macrophages (key cells), lymphocytes and plasma cells, eosinophils
Describe necrosis in chronic inflammation
Not as prominent a feature as in acute inflammation
Describe the destruction of parenchyma in chronic inflammation
Loss of functional tissue, with repair by fibrosis
Describe the formation of granulation tissue in chronic inflammation
1. Highly vascular tissue composed of blood vessels and activated fibroblasts
a. Blood vessels derive from preexisting blood vessels (angiogenesis)
b. Essential for normal wound healing
c. Precursor for scar formation
2. Fibronectin is required for granulation tissue formation
a. Cell adhesion glycoprotein located in the ECM
-Binds to collagen, fibrin, and cell surface receptors (eg integrins)
b. Chemotactic factor that attracts fibroblasts (synthesize collagen) and endothelial cells 9form new blood vessels, angiogenesis)
-Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF) are important in angiogenesis
Describe granulomatous inflammation
Specialized type of chronic inflammation
Describe the infectious causes of granulomatous inflammation
1. Examples: TB and systemic fungal infection (eg histoplasmosis)
2. Usually associated with caseous necrosis (ie soft granulomas)
-Caseation is due to lipid released from the cell wall of the dead pathogen
Contrast the pathogenesis of acute and chronic inflammation
Acute: Microbial pathogens, trauma, burns
Chronic: Persistent acute inflammation, foreign bodies (eg silicone, glass), autoimmune disease, certain types of infection (eg TB, leprosy)
Contrast the primary cells involve in acute and chronic inflammation
Acute: Neutrophils
Chronic: Monocytes/macrophages (key cells), B and T lymphocytes, plasma cells, fibroblasts
Contrast the primary mediators in acute and chronic inflammation
Acute: Histamine (key mediator), prostaglandins, leukotrienes
Chronic: Cytokines (eg IL-1), growth factor
Contrast the necrosis in acute and chronic inflammation
Acute: Present
Chronic: Less prominent
Contrast the scar tissue of acute and chronic inflammation
Acute: Absent
Chronic: Present
Contrast the onset of acute and chronic inflammation
Acute: Immediate
Chronic: Delayed
Contrast the duration of acute and chronic inflammation
Acute: Few days
Chronic: Weeks, months , years
Contrast the outcome of acute and chronic inflammation
Acute: Complete resolution, progression to chronic inflammation, abscess formation
Chronic: Scar tissue formation, disability, amyloidosis
Contrast the main immunoglobulin of acute and chronic inflammation
Acute: IgM
Chronic: IgG
Contrast the serum protein electrophoresis effect in acute and chronic inflammation
Acute: Mild hypoalbuminemia
Chronic: Polyclonal gammaopathy; greater degree of hypoalbuminemia
Contrast the peripheral blood leukocyte response of acute and chronic inflammation
Acute: Neutrophilic leukocytosis
Chronic: Monocytosis
Describe the non-infectious causes of granulomatous inflammation
1. Examples: Sarcoidosis and Crohn’s disease
2. Noncaseating (ie, hard granulomas)
Describe the morphology of granulomatous inflammation
1. Pale, white module with or without central caseation
2. Usually well circumscribed
3. Cell types
a. Epithelioid cells (activated macrophages), mononuclear (round cell) infiltrate (CD4 helper T cells, or Th cells of the Th1 type)
b. Multinucleated giant cells formed by fusion of epithelioid cells
-Nuclei usually located at the periphery
4. TNF-alpha is important in the formation and maintenance of TB and systemic fungal granulomas
a. TNF-alpha and gammaIFN recruit cells for granuloma formation
b. TNF-alpha inhibitors cause the breakdown of granulomas leading to dissemination of disease
5. Pathogenesis of a TB granuloma