Pathology - Inflammation
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- 5 cardinal signs of inflammation?
- Rubor (red), dolor (pain), calor (hot), tumor (swelling), functio laesa (loss of fn)
- 3 families of adhesion molecules involved in acute inflammation?
- Selectins, immunoglobulin-family adhesion proteins, integrins
- What are the steps in neutrophil margination and adhesion during inflammatory response?
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1) Margination
2) Rolling
3) Activation
4) Adhesion
5) Transmigration - What occurs during "margination"?
- neutrophils line vessel walls due to increased blood viscosity due to fluid extravasation
- What occurs during "rolling"?
- E- and P-selectins on endothelial cells bind weakly to neutrophils
- What occurs during neutrophil "activation" and "adhesion"?
- neutrophils are stimulated by chemokines to express their integrins, which firmly adhere to immunoglobulin-family adhesion proteins on endothelial cells (ICAMs)
- What occurs during neutrophil "transmigration"?
- leukocytes move between endothelial cells, and migrate through basement memb towards inflammatory stim (chemotaxis)
- What is chemotaxis?
- when leukocytes are attracted to and move toward an injury, moves along a chemical gradient
- Chemotactic factors?
- Chemokines (IL-8), C5a, finbrinopeptides, leukotriene B4 (LTB4), formyl methyl peptides
- Hemodynamic changes in acute inflammatory response?
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1. Transient initial vasoconstriction, followed by massive vasodilation
2. Increased vascular permeability (due to endothel cell contraction or injury) -> leakage of proteinaceous fluid -> edema
3. Blood stasis due to increased viscosity -> facilitates neutrophil margination - Causes of NEUTROPHILIA?
- BACTERIAL infections, and other causes of ACUTE INFLAMMATION, such as infarction (usu w/in 1st 24hrs); EARLY RELEASE from bone marrow reserve pool
- Causes of MONOCYTOSIS?
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TB, brucellosis, typhus, salmonella (seen w/CHRONIC INFLAMMATION)
Replace neutrophils after 2-3 days, are longer lived, can divide/proliferate in tissue - Causes of LYMPHOCYTOSIS?
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VIRAL infections (influenza, mumps, rubella, infectious mononucleosis)
BACTERIAL infections (whooping cough and TB)
**prominent in CHRONIC INFLAMMATION - Causes of EOSINOPHILIA?
- ALLERGIC reactions and PARASITIC infections, also in polyarteritis nodosa and Hodgkin lymphoma
- Causes of BASOPHILIA?
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chronic myelogenous leukemia and other myeloproliferative diseases
(mast cells and basophils are source of histamine) - Key steps in phagocytosis?
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1. engulfment of opsonized particle by macrophage or neutrophil, forming phagosome
2. fusion with lysosome to make phagolysosome
3. digestion - What are the most important opsonins in phagocytosis?
- IgG subtypes and C3b
- Types of intracellular microbial killing in phagocytosis?
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Oxygen dependent:
1. NADPH oxidase-dependent
2. myeloperoxidase-dependent
Oxygen independent:
1. lysosome-dependent - Basic mechanism of killing in oxygen-dependent microbial killing during phagocytosis?
- H2O2 (and other free radicals) are produced/activated, and disrupt cell walls
- Endogenous mediators of acute inflammation?
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1. Vasoactive amines
2. Arachidonic acid metabolites
3. Cytokines
4. Kinin system
5. Complement system
6. Nitric oxide - Effects of HISTAMINE?
- vasodilation and increased vascular permeability
- Where is histamine released from?
- Basophils, mast cells, platelets
- What triggers release of histamine from PLATELETS?
- is liberated by platelet aggregation and release reaction, which is triggered by 1)endothelial injury and thrombosis, or 2)platelet activation factor (PAF)
- What triggers the release of histamine from MAST CELLS or BASOPHILS?
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1. antigen binds to IgE on mast cell/basophil
2. C3a or C5a (ANAPHYLATOXINS) bind to receptors on mast cell/basophil
3. physical stimuli (heat/cold)
4. IL-1 (cytokines) - What substances does PAF release, and what other effects does it have?
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1. releases histamine and 5HT from platelets
2. vasoactive and bronchospastic effects
3. activates arachidonic acid - What does VASOACTIVE mean?
- causing constriction or dilation of blood vessels
- What is a VASOACTIVE AMINE?
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acts on blood vessels to alter permeability or to cause vasodilation
e.g. histamine and 5HT - What are the 2 ARACHIDONIC ACID PATHWAYS?
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1. cyclooxygenase pathway
2. lipooxygenase pathway - What are the general effects of arachidonic acid metabolites?
- short range hormones that rapidly decay, they mainly affect inflammation and hemostatis via vasodilation/vasoconstriction, platelet aggregation, etc
- What 2 enzymes catalyze the cyclooxygenase pathway?, and which one is expressed in gastric mucosa?
- COX-1 (in gastric mucosa) and COX-2
- What substances inhibit the catalysts of the cyclooxygenase pathway, and via what mechanism?
- aspirin and other NSAIDs inhibit prostaglandin synthesis (prostaglandin is the intermediate between arachidonic acid and TXA2,PGI2,PGD2,PGE2,PGF2)
- What might be the benefit of selective COX-2 inhibitors?
- actions of COX-1 in gastric mucosa are preserved, thus avoiding anti-inflammatory effects in gastric mucosa, and preventing gastric ulceration
- What are the three classes of products of the cyclooxygenase pathway?
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1. (Platelet) Thromboxane A2 (TXA2)
2. (Endothelial) Prostacyclin (PGI2)
3. PGD2, PGE2, PGF2 - What are the opposing functions of TXA2 and PGI2?
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TXA2: IN PLATELETS, promotes platelet aggregation and vasoconstriction
PGI2: IN ENDOTHELIUM, inhibits platelet aggregation and causes vasodilation - What are the functions of PGD2, PGE2, and PGF2?
- vasodilation (plus pain for PGE2)
- Products of lipooxygenase pathways?
- leukotriene B4 (LTB4), LTC4, LTD4, LTE4
- What is the function of LTB4?
- neutrophil chemotaxis
- What is the function of LTC4, LTD4, LTE4?
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vasoconstriction, bronchospasm, increased permeability
"slow-reacting substance of anaphylaxis" (SRS-A) - Common cytokines involved in inflammation?
- IFN-gamma (activates monocytes), IL-1 & TNF (s/c by monocytes)
- Main cytokine effects on inflammation?
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1. Systemic effects (fever, leukocytosis)
2. Hepatic synthesis of acute phase proteins
3. Synthesis of adhesion molecules
4. Neutrophil degranulation
5. Promote thrombosis - What is the important peptide product of the kinin system that plays a role in inflammation?
- bradykinin
- What are the 2 cascade reactions necesesary to create bradykinin?
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1. Hageman factor (factor XII) converts prekallikrein -> kallikrein
2. Kallikrein converts high molecular weight kininogen (HMWK) -> bradykinin - What are the effects of BRADYKININ?
- increase vascular permeability, pain, vasodilation, bronchoconstriction
- Which complement proteins participate in inflammatory response?
- C3a & C5a, C3b, C5b-C9
- What is an ANAPHYLATOXIN?
- mediate degranulation of basophils and mast cells w/release of histamine (e.g. C3a and C5a)
- What are the 4 functions of C5a?
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1. anaphylatoxic effect
2. chemotactic effect on neutrophils
3. induces expression of leukocyte adhesion molecules
4. activates lipooxygenase pathway of arachidonic acid metabolism - What is the function of C3b?
- opsonization of invader for phagocytosis by neutrophil/macrophage
- What is the function of C5b-C9?
- Forms membrane attack complex (MAC) = lytic agent for bacteria and other cells
- What are the 3 main functions of the complement cascade?
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1. opsonization of pathogens (C3b)
2. recruitment of inflammatory cells (C3a, C5a)
3. killing of pathogens (C5b-C9) - What are the effects of NITRIC OXIDE during the inflammatory process?
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produced by endothelial cells; smooth muscle relaxation (controls vasc tone), inhibits platelet aggregation, increased vascular permeability
aka endothelium-derived relaxing factor - What triggers the ALTERNATIVE PATHWAY of complement activation?
- bacterial surface
- What triggers the CLASSICAL PATHWAY of complement activation?
- antigen-antibody complex (IgG or IgM)
- What molecules are unique to the alternative pathway?
- C3, factors B and D -> C3 converatse
- What molecules are unique to the classical pathway?
- C1, C2, C4 -> C3 convertase
- 3 potential outcomes of acute inflammation?
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1. restoration of tissue and function
2. tissue destruction and persistent acute inflammation
3. conversion to chronic inflammation - 4 ways that tissue destruction from acute inflammation can manifest itself?
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1. abscess
2. ulcer
3. fistula
4. scar - What are the characteristics of an ABSCESS?
- filled w/pus (neutrophils, monocytes, liquefied cellular debris), walled off by fibrous tissue, results from tissue destruction by lysosomal products, usu caused by bacterial infections
- What is the "final result" of tissue destruction?
- Scar, w/resultant distortion of structure, and sometimes altered function
- What histological changes occur when acute inflammation becomes chronic?
- replacement of neutrophils and monocytes w/lymphocytes, plasma cells, and macrophages; proliferation of fibroblasts and new vessels, w/scarring and architectural distortion
- What are the 3 major diseases caused by defects of neutrophils?
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1. Chronic granulomatous disease (CGD)
2. Chediak-Higashi syndrome
3. Leukocyte adhesion deficiency (LAD) - Molecular defect in CHRONIC GRANULOMATOUS DISEASE (CGD)?
- deficiency of NADPH OXIDASE, thus failure to generate superoxide anion and other O2 radicals -> oxygen-dependent microbial killing cannot proceed
- Histologic marker of CGD?
- phagocytes that ingest but do not kill certain microorganisms
- Symptoms of CGD?
- recurrent infections w/catalase-positive bacteria and fungi
- Why is a person w/CGD still protected from catalase-negative organisms?
- catalase-negative organisms produce sufficient H2O2 to permit oxygen-dependent microbicidal mechanisms to proceed (catalase negative organisms destroy H2O2)
- Molecular defect in CHEDIAK-HIGASHI SYNDROME?
- granule structural defect
- Markers for CHEDIAK-HIGASHI SYNDROME?
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abnormal white blood cells:
-chemotactic defects
-degranulation defects
-large cytoplasmic granules caused by impaired fusion of lysosomes - Symptoms of CHEDIAK-HIGASHI SYNDROME?
- absent NK activity, partial albinism, cranial/peripheral neuropathy, repeated infections
- Molecular defect of LEUKOCYTE ADHESION DEFICIENCY (LAD)?
- absence of CD18--common beta chain of leukocyte integrins; interferes with neutrophil adhesion and transmigration
- Symptoms of LEUKOCYTE ADHESION DEFICIENCY (LAD)?
- recurrent chronic infections, failure to form pus, does not reject umbilical cord stump
- 2 major patterns of CHRONIC INFLAMMATION?
- Chronic nonspecific inflammation, granulomatous inflammation
- Chronic inflammation commonly arises in what 3 settings?
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1. persistent infections
2. autoimmune diseases
3. prolonged exposure to toxic agents - 3 common histologic markers of chronic inflammation?
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1. collection of chronic inflammatory cells (macrophages, lymphocytes, plasma cells)
2. tissue destruction
3. repair involving angiogenesis and fibrosis - Who activates what in CHRONIC NONSPECIFIC INFLAMMATION?
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-MONOCYTES recruited by chemotactic factors
-MONCYTES/MACROPHAGES secrete cytokines, which activate LYMPHOCYTES
-LYMPHOCYTES then secrete additional cytokines that activate MONOCYTES/MACROPHAGES
-MACROPHAGE presents antigen to activate B LYMPHOCYTE, which forms antibody-producing PLASMA CELLS - What is a GRANULOMA?
- collection of activated macrophages that have an enlarged, squamous cell-like (EPITHELIOD) appearance
- What disease is characterized by CASEATING GRANULOMAS?
- TB
- What disease is characterized by NONCASEATING GRANULOMAS?
- sarcoidosis