Acute inflammation 4
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Transcript of Acute inflammation 4
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Acute inflammation 4
By Dr. S. Homathy
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Phagocytosis -Engulfment
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Contact, Recognition, Internalisation. Opsonins: e.g. Fc and C3b receptors Cytoskeletal changes (as with chemotaxis);
‘zipper’ effect.
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Phagocytosis – Killing and Degradation
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Killing / DegradationOxygen indepenent
killing• Bactericidal
permeability increasing protein
• Lysozyme• Major basic protein • defensin
Oxygen depenent killing
• NADPH oxidase activated; produces superoxide ion.
• This converts to hydrogen peroxide.
• H2O2-Myeloperoxidase-halide system: produces HOCl. (i.e. bleach!) a powerful oxident and antimicrobial agent
• Myeloperoxidase independent:– Uses superoxide and hydroxyl
radicals. Less efficient.
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Oxidative burst
• Phagocytosis trigger oxidative burst• Characterized by a sudden increased in – oxygen consumption– Glycogen catabolism– Increased glucose oxidation– Production of reactive oxygen metabolites.
(Formation of superoxide ion)• 2O2 + NADPH 2O
.
2-rad + NADP+ + H+
(NADPH oxidase)
• O.
2 + 2H+ H2O2 (dismutase)
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• Hydrogen peroxide alone insufficient
• MPO (azurophilic granules) converts hydrogen peroxide to HOCl- (in presence of Cl- ), an oxidant/antimicrobial agent
• Therefore, PMNs can kill by halogenation, or lipid/protein peroxidation
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• Reactive end-products only active within phagolysosome
• Hydrogen peroxide broken down to water and oxygen by catalase
• Dead microorganisms degraded by lysosomal acid hydrolases
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Leukocyte activation. Different classes of cell surface receptors of leukocytes recognize different stimuli. The receptors initiate responses that mediate the functions of the leukocytes.
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Myocardial infarct - neutrophil infiltration
Deadmyocytes
Neutrophils
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Leukocyte-induced tissue injury
• Destructive enzymes may enter extracellular space in event of:– Premature degranulation– Frustrated phagocytosis (large, flat)–Membranolytic substances (urate crystals)– Persistent leukocyte activation (RA, emphysema)
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Defects of leukocyte functionGenetic defects
• Defects of adhesion:– LFA-1 and Mac-1 subunit defects lead to impaired
adhesion (LAD-1)– Absence of sialyl-Lewis X, and defect in E- and P-
selectin sugar epitopes (LAD-2)
• Defects of chemotaxis/phagocytosis:–Microtubule assembly defect leads to impaired
locomotion and lysosomal degranulation (Chediak-Higashi Syndrome)
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• Defects of microbicidal activity:– Deficiency of NADPH oxidase that generates
superoxide, therefore no oxygen-dependent killing mechanism (chronic granulomatous disease)
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Acquired defects
• Defects in chemtaxis-– Malignancy, sepsis, diabetes
• Defects in adhesion– Haemodialysis, DM
• Decreased phagocytosis and microbicidal activity– Leukaemia, sepsis, DM, malnutrition
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Fibrin formation in inflammation
• Fibrinogen in the exudates is converted to fibrin
• This will form a barrier which localizes the inflammatory reaction
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Fibrinous pericarditis
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Role of lymphatics in inflammation
• The lymphatics are dilated
• exudates passes, between endothelial cells into the lymphatics
• Some of the lymphatics may be secondarily inflamed (lymphangitis)
• The draining lymph nodes may be inflamed
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Summary of the acute inflammatory reaction
1. Transient vasoconstriction2. Vasodilation: Increased blood flow3. Increased vascular permeability: Exudation4. Reduced blood flow and stasis5. Diapedesis of RBC6. Margination, adhesion and emigration of
PNL7. Phagocytosis8. Formation of fibrin
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Chemical mediators
• Chemical substances synthesized or released and mediate the changes in inflammation
–May be circulating in plasma or–May be produced locally at the site of
inflammation by cells.
• Most mediators induce their effects by binding to specific receptors on target cells.
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• Mediators may stimulate target cells to release secondary effector molecules
• May act only on one or a few targets or may have widespread activity.
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• Mediator function is tightly regulated.– Once activated and released from the cell, most
mediators • quickly decay (AA metabolites)• are inactivated by enzymes (kininase)• are eliminated or inhibited (antioxidants)
• A major reason for the checks and balances is that most mediators have the potential to cause harmful effect
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Reactions are similar irrespective of tissue or type of injury
Reactions occur in absence of nervous connections
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Chemical mediators of inflammation
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• Plasma-derived:– Complement, kinins, coagulation factors–Many in “pro-form” requiring activation
(enzymatic cleavage)
• Cell-derived:– Preformed, sequestered and released (mast cell
histamine)– Synthesized as needed (prostaglandin)
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Specific mediatorsVasoactive amines
• Histamine: –Vasodilation ( principal mediator of
immediate phase reaction) –venular endothelial cell contraction,– junctional widening; – Inactivated by histaminase
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• released by mast cells, basophils, platelets in response to – injury (trauma, heat), – immune reactions (IgE-mast cell FcR), –anaphylatoxins (C3a, C5a fragments), –cytokines (IL-1, IL-8),– neuropeptides, – leukocyte-derived histamine-releasing
peptides