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34 Cards in this Set
- Front
- Back
Cardinal signs of inflammation |
Function laesa – loss of fxn Rubor – redness Tumor – swelling Calor – heat Dolor – pain |
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Inflammatory response in general |
= complex rxn to injuries caused by microbes, damaged cells (tissue-based startle rxn to trauma) - consists of vascular responses, migration, activation of leukocytes, systemic rxns Innate immunity -> DC's -> adaptive immunity (T cells) |
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Purposes of inflammation |
- recruitment & equipment of other cells
- liquefication of surrounding tissue --| microbial metastasis - beginning of the healing process |
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Pathology of inflammation |
- Tissue dmg due to inflammatory response - Aggregates of chronically activated lymphocytes & macrophages -> granuloma --| organ fxn - Distortion of the repair mechanism (fibrosis) - Neoplastic transformation -> cancer |
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Chemical mediators of inflammation - origins |
- Already present in circulation (plasma) - zymogens -> cleavage -> active (complement & coagulation cascades, inhibitors) - Cell-derived - rapid release: pre-synthesized & present in cells (histamine) - Cell-derived - slow release: require de novo synthesis (LPS -> cytokines) |
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Chemical mediators of inflammation - mechanisms of activity |
- Binding to specific R's (chemokines, cytokines) - Direct enzymatic activity (lysosomal proteases) - Oxidative damage induction (H2O2) (- Regulation) |
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Leukocyte extravasation |
Selectins -> rolling Integrins -> adhesion, diapedesis - α & β chain dimers - regulated by chemokines |
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Histamine |
- synthesized & stored in mast cells in CT (also in basophils & platelets) - physical stimuli, immunobiological signals -- IgE x-linking -- anaphylatoxin signaling (C3a, C5a) -- cytokines (IL-1) -- chemokines (IL-8) -> release -> H(1)-R -> vasodilation, permeability |
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Serotonin |
- stored in platelets -> aggregation -> release -> ↑ vascular permeability |
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Complement |
- mediates humoral immunity & inflammation - role in cytolysis (MAC), opsonization, solubilization & clearance of Ab-Ag complexes - constitutes of proteolytic enzymes - Ab/pathogens -> activaion -> amplification - C3a & C5a: anaphylatoxins -> histamine release - C5a: chemotaxis, adhesion, lipoxygenase pwy |
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Eicosanoids |
- local hormones (leukotriens, prostaglandins, lipoxins) produced via arachidonic A cascade; rapid & short λ - formed in lipid bodies; tissue-restricted - COX-1/2 pwy -> prostaglandins - lipoxins require >1 type of cell for sunthesis -> restricted to sites of inflammation |
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Chemokines |
- activate & chemoattract leykocytes, integrin adhesion; spatial & temporal resolution - 4 classes based on cys residue relative placement: CXC (α), CC (β), C (γ), CxxxC - produced by macrophages & endothelium -> proteoglycans -> gradient - bind to 7-TM R's = GPCR's - specificity & promiscuity |
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NO (nitric oxide) |
- Ca++ influx -> released from endothelial cells - short λ, potent paracrine vasodilator - binds to hemoglobin (NO sink?) - produced from L-Arg by NOS: e-NOS, n-NOS ~ constitutively made but inactive (Ca++); iNos ~ inducible, produced by macrophages (IFN-γ) - non-specific reactive species x IC bacteria |
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Platelet Activating Factor (PAF) |
= lipid molecule -> ↑ vascular permeability, cell aggregation, adhesion, chemotaxis - binds to ligand-specific 7 TM GPCR's |
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Cytokines |
- produced by WBC's - mediate inflammatory responses - macrophages activation -> IL-1, TNF-α -> R's -> NF-κB -> fever, sleep, loss of appetite, ↑ acute phase proteins, hemodynamic effects (shock), neutrophilia, endothelium activation, PGI synthesis, endothelial cytokine production, fibroblast proliferation, collagen synthesis |
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Therapeutic interventions |
- glucocorticoids -> I-κB - aspirin --| COX-2 & I-κB degradation --| NF-κB - humira --| TNF-α |
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Acute inflammation |
= rapid host response that serves to deliver leukocytes & plasma proteins (Ab's, etc.) to sites of infection or tissue injury; major components: - increase in blood flow - structural changes -> proteins & leukocytes leave the circulation -> accumulation @ the site of injury |
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Sequence of events in acute inflammation |
- Stimulus infections (bacterial, viral, fungal, parasitic), tissue necrosis, foreign bodies, immune rxns - Vascular changes - BF & caliber, vascular permeability, lymph drainage - Leukocyte extravasation & chemotaxis = exudate (fluid & protein leakage) -> swelling (edema); margination; cytokines & chemokines - Recognition & removal of offending agents - phagocytosis, engulfment, killing, degradation - Termination - regeneration / repair |
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Mechanisms of exudative edema |
- retraction of endothelial cells - endothelial injury (burns) - leukocyte-mediated vascular injury - ↑ transcytosis (<- VEGF) |
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Adhesion molecules |
Selectins - P-selectin (platelets, endothelium), E-selectin (endothelium), L-selectin (leukocytes); bind: Glycoproteins - PRGL-1, ESL-1, CD34, Glycam-1 Immunoglobulins (endothelium) - ICAM-1, VCAM-1, PECAM-1 (CD31); bind: Integrins (leukocytes) - LFA-1, MAC-1, VLA-4 (αβ) |
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Transmigration |
(= diapedesis) Chemokines -> leukocytes: => express PECAM-1 (CD31) -> migration through interendothelial spaces - secrete collagenase -> cross BM - adhere to ECM (via integrins & CD44) |
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Chemotaxis |
= locomotion along a chemical gradient Exogenous - bacterial products (peptides, lipids) Endogenous - chemical mediators (cytokines [IL-8], complement [C5a], Arachidonic A metabolites [LTB4]) -> bind to G-proteins on surface of leukocytes -> polymerization of actin |
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Nature of inflammatory infiltrate over time |
- Edema (0-6 hrs) - PMN's (6-24 hrs) -- Neutrophils: infections, infarcts -- Eosinophilia: allergy, asthma, parasite -- Lymphocytosis: viral - Monocytes, macrophages (24-48 hrs) |
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Recognition of microbes & dead tissue |
TLR's - recognize bacterial/viral products, stimulate microbicidal substances & cytokines GPCR's - recognize bacterial peptides, chemokines, lipid mediators; induce migration & activate microbicidal respiratory burts Opsonin R's - recognize opsonins (IgG, C3b, etc.) Cytokine R's - recognize IFN-γ |
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Phagocytosis & engulfment |
Recognition & attachment: - opsonin R's - mannose R's - scavenger R's Engulfment - phagosome formation -> fusion w/ lysosome => phagolysosome - mediated by polymerization of actin filaments |
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Killing & degradation |
- Respiratory burst = coupling of phagocytosis & rapid oxidative rxn -> ROS w/in the lysosome - Activating stimuli => cytosolic proteins localize to lysosomal membrane -> form phagocyte oxidase -> ox. NADPH & red. O2 -> superoxide - NOS induced => Arg -> NO - other substances in leukocyte granules (lysozyme, elastase, MBP, ...) |
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Collateral damage |
Normal - appropriate defense rxn against difficult to eradicate pathogens (TB, virus) Autoimmunity - inappropriate defense rxn X host tissue (RA, Goodpasture's syndrome) Allergy - excessive defense X harmless environmental substances (asthma) Toxic agents - prolonged exposure to non-degradable exogenous/endogenous toxic agents |
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Defects in leukocyte fxn |
LAD (defective adhesion molecules) -> recurrent bacterial infections CGD - catalase + organisms -> ingested but not killed - catalease - org. -> bacterial metab. -> H2O2 Chediak-Higashi syndrome (LYST) - defective fusion of phagosomes & lysosomes |
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Defects in leukocyte fxn |
Bone marrow suppression - leukemic infiltrate - radiation, chemotherapy - aplastic anemia (idiopathic, autoimmune, ...) Chronic disease - diabetes, malignancy, sepsis, dialysis |
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Termination |
Passive - neutrophils & mediators are short-lived & are degraded Active - AA metabolites: pro-inflammatory -> anti- - macrophages (M2): anti-inflam. cytokines - anti-inflammatory lipid mediators - n. impulses (ACh) --| macrophage (M1) TNF |
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Chronic inflammation |
- Prolonged iInflammation where tissue injury & repair attempts coexist - characterized by mononuclear (lymphocytes, plasma cells, macrophages) cell infiltrate, tissue destruction, angiogenesis, fibrosis - unresolved acute infl. -> crhonic low-grade -> carcinogenesis & degenerative diseases |
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Causes of chronic inflammation |
Persistent infections - delayed type hypersensitivity rxn X difficult to eradicate path'. Immune-mediated inflammatory disease - autoimmunity, allergy Prolonged exposure to toxic agents - endogenous/exogenous |
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Cells of chronic inflammation |
Macrophage: tissue -> activated -> M1 (inflammatory)/M2 (restorative) T-cells - CD4+ & macrophages, CD8+ (viral) B-cells -> lymphoid follicles Plasma cells - produce Ab X perssistent Ag's |
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Granuloma |
= collection of macrophages - often appear "epitheloid" ~ transformed - contain fused giant cells: -- Lagerhans-type (peripheral nuclei) -- foreign body-type (random nuclei) - surrounded by a "collar" of lymphocytes & plasma cells |