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Inflammation

Inflammation. Dr. Ahmad Hameed MBBS,DCP, M.Phil. Cytokines. Polypetide products of many cell types that function as mediators of inflammation and immunity Some stimulate bone marrow precursors to produce more WBCs Some mediate communication between WBCs(Interleukins)

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Inflammation

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  1. Inflammation Dr. Ahmad Hameed MBBS,DCP, M.Phil

  2. Cytokines • Polypetide products of many cell types that function as mediators of inflammation and immunity • Some stimulate bone marrow precursors to produce more WBCs • Some mediate communication between WBCs(Interleukins) • Major cytokines in acute inflammation(TNF, IL-1) and chronic inflammation (IFN-γ ,IL-12)

  3. TNF & IL-1 • Produced by macrophages, mast cells, endothelial cells • Stimulated by microbial products, immune complexes, products of T-lymphocytes • Endothelial effects • Endothelial activation expression of adhesion molecules • WBC binding & recruitment • Procoagulant activity by TNF • Increase in IL-1,IL-6,IL-8,PDGF, eicosanoids • Fibroblast effects • Activates tissue fibroblasts • Increases proliferation, production of collagen &ECM

  4. Systemic Effects • Fever • Lethargy • Increased sleep • Decreased appetite • Hepatic synthesis of acute phase proteins • Metabolic wasting • Corticosteroids Synthesis • Neutrophil release in circulation • Fall in blood pressure

  5. The roles of cytokines in acute inflammation. The cytokines TNF, IL-1, and IL-6 are key mediators of leukocyte recruitment in local • inflammatory responses and also play important roles in the systemic reactions of inflammation.

  6. Chemokines • Family of small 8-10 kDa proteins • Helps in recruitment and activation of Leukocytes • Responsible for anatomic distribution of B & T lymphocytes in different areas of lymph nodes & spleen • Mediate their activities by binding to specific G-protein coupled receptors on target cells. • Receptors: CXCR4, CCR5

  7. Chemokines • CXC • One amino acid separating the cysteines • Act primarily on neutrophil • IL-8 • Produced by macrophages, endothelial cells, mast cells, fibroblasts • Produced in response to microbial products, IL-1 and TNF • CC • Adjacent cysteine residues • MCP-1, MIP-1α • RANTES • Eotaxin

  8. ROS • Produced by NADPH oxidase in neutrophils & macrophages • Activated by microbes, immune complexes, cytokines • With in lysosome destroy phagocytosed microbes and nectrotic cells • At low levels, increases cytokines & adhesion molecule expression ,destroy phagocytosed microbes & necrotic tissues • At high levels, cause tissue injury by endothelial damage, breakdown of ECM because of protease activation and an • Direct injury to other cell types ,inactivation of anti-proteases • Protective mechanisms( Catalase, Superoxide dismutase & Glutathione)

  9. NO • Short lived, soluble, free radical gas • Produced by neurons, macrophages & endothelial cells • nNOS, iNOS(IL-1, TNF, IFN-γ, bacterial endotoxins) also present hepatocytes, cardiac myocytes, resp epithelial cells, eNOS • Functions • Cytotoxic to microbes(Microbicidal) • Vasodialation • ↑ Increase vascular permeability • Inhibits platelet adhesion,aggregation & degranulation • Inhibits WBC adhesion & recruitment • ↓ Decrease cellular response

  10. Lysosomal Enzymes of WBCs • Capable of phagocytosis and tissue damage • Acid proteases • Active only within phagolysosomes • Neutral proteases • E.g. Elastase,Collagenase,Cathepsin • Active in ECM, degrade elastin, collagen & other matrix proteins • Convert C3 & C5 to C3a & C5a • Can convert HMWK to Bradykinin

  11. Destructive Effects of Lysosomal Enzymes • Proteases are checked by Anti-proteases e.gα1-antitrypsin is inhibitor of neutrophilelastase and α2 – macrogloblin • α1-antitrypsin deficiency in the lungs cause severe panacinar emphysema

  12. Neuropeptides ( e.g Substance P) • Initiates inflammation • Transmit pain signals • Regulate vessel tone & thus vascular permeability • Secreted by sensory nerves (lungs, GIT) and leukocytes. • Stimulation of secretion by endocrine cells • Regulate blood pressure

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