Chemical mediators of inflammation

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Chemical mediators of inflammation

  1. 1. ChemicalMediators ofInflamationBy: Ahsan Shafiq Page 1
  2. 2. Origin• Locally by cells(cell derived mediators)• Liver – Inactive precursors in plasma(plasma protein derived mediators) Page 2
  3. 3. Cell derived Mediators• Preformed in secretory granules→Vasoactive Amines e.g Histamine, serotonin• Newly Synthesized a. Arachidonic Acid Metabolites(PGS, PGI2, TXA2, LTS, LXS) b. TNF, IL-1 c. Cytokines d. ROS e. NO f. Neuropeptides g. PAF h. Lysosomal Enzymes of WBCs Page 3
  4. 4. Plasma Protein Derived mediators • Complement System • Coagulation & Kinin System Page 4
  5. 5. Cell Derived Mediators• Histamine • Produced by circulating basophils, platelets & massed cells adjacent to vessels • Produced in response to physical injury,immune reactions, neuropeptides, C3a & C5a, Cytokines, WBC-derived Histamine releasing protein • Vasodilatation, Increase vascular permeability, Endothelial activation Page 5
  6. 6. Cell Derived Mediators• Serotonin • Produced mainly within platelets dense body granules • Released during platelet aggregation • Cause vasodilatation, Increase vascular permeability Page 6
  7. 7. Cell Derived Mediators• AA Metabolites – Cyclooxygenase pathway • PGD2,PGE2,PGF2α – V.D – Potentiates Edema formation • PGI2 – Produced by prostacyclin synthase in endothelial cell – V.D, Inhibits Platelet aggregation • TxA2 – Produced by Thromboxane synthase in pllatelets – V.C & stimulates platelets aggregation Page 7
  8. 8. Cell Derived Mediators– Lipoxygenase Pathway • LTB4 – Produced by neutrophils & some macrophages – Chemotactic agent for neutrophils • LTC4,LTD4 & LTE4 – Produced by mast cells – V.C bronchospasm • Lipoxins – Endogenous antagonists of Leukotrienes Page 8
  9. 9. Cell Derived Mediators• PAF • Produced by WBCs & endothelial cells • Causes V.C, Bronchoconstriction Page 9
  10. 10. Cell Derived Mediators• Cytokines – Some stimulate bone marrow precursors to produce more WBCs – Some mediate communication between WBCs(Interleukins) – Some play role in inflammation(TNF, IL-1, Chemokines, IFN-γ ,IL-12) Page 10
  11. 11. Cell Derived Mediators• TNF & IL-1 – Endothelial effects • Endothelial activation • WBC binding & recruitment • Procoagulant activity • Increase in IL-1,IL-6,IL-8,PDGF eicosanoids – Fibroblast effects • Activates tissue fibroblasts • Increases proliferation • Production of collagen &ECM Page 11
  12. 12. Cell Derived Mediators– Systemic Effects • Fever • Lethargy • Increased sleep • Decreased appetite • Hepatic synthesis of acute phase proteins • Metabolic wasting • Corticosteroids Synthesis Page 12
  13. 13. Cell Derived Mediators• Chemokines – Helps in recruitment of Leukocytes – Responsible for anatomic distribution of B & T lymphocytes in different areas of lymph nodes & spleen Page 13
  14. 14. Cell Derived Mediators• ROS – Produced by NADPH oxidase in neutrophils & macrphages – 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 & direct injury to other cell types – Protective mechanisms( Catalase, Superoxide dismutase & Glutathione) Page 14
  15. 15. Cell Derived Mediators• NO – Produced by neurons, macrophages & endothelial cells – nNOS, iNOS (IL-1, TNF, IFN-γ, bacterial endotoxins),eNOS – Functions • V.D • Inhibits platelet adhesion,aggregation & degranulation • Inhibits WBC adhesion & recruitment • Cytotoxic to microbes(Microbicidal) Page 15
  16. 16. Cell Derived Mediators• Lysosomal Enzymes of WBCs – Acid proteases • Active only within phagolysosomes – Neutral proteases • Elastase,Collagenase,Cathepsin • Active in ECM • Degrade elastin, collagen & other matrix proteins • Convert C3 & C5 to C3A & C5A • Can convert HMWK to Bradykinin Page 16
  17. 17. Cell Derived Mediators• Neuropeptides ( e.g Substance P) – Transmit pain signals – Regulate vessel tone & thus vascular permeability Page 17
  18. 18. Plasma Protein derived mediators • Complement System – Consists of Plasma proteins – Upon activation different complement proteins(C3b) coat/opsonize microbes for phagocytosis & destruction – C3a & C5a cause mass cells to release histamine which inturn causes V.D thus increasing vascular permeability – C5a activates lipoxygenase pathway causing release of more inflammatory mediators – C5a also helps in leukocyte activation, adhesion & chemotaxis Page 18
  19. 19. Plasma Protein derived mediators • Coagulation & Kinin System – Hageman factor/Factor12a • A protein synthesized by liver • Circulates in an inactive form in plasma • Activated by collagen basement membrane or activated platelets • Activated with the help of HMWK & kallikrein • Activated factor12 further activates – Kinin System – Clotting System – Fibrinolytic System – Complement System Page 19
  20. 20. Plasma Protein derived mediators • Kinin System – Ultimately leads to formation of bradykinin – Bradykinin causes arteriolar dilation, increases vascular permeability & broncho constriction • Clotting System – 12a → 11a → 10a → 2a (Thrombin) – Thrombin converts fibrinogen into fibrin & generates fibrinopeptides – Fibrinopeptides → Increased Vascular permeability & chemotactic for WBCs Page 20
  21. 21. Plasma Protein derived mediators • Fibrinolytic System – Ultimately leads to formation of plasmin – Plasmin • converts C3 to C3a • Converts factor-12 to factor-12a • Breaks down fibrin to fibrin degradation products which further increases the vascular permeability Page 21
  22. 22. Plasma Protein derived mediators • Complement System – Mainly leads to the formation of C3a & C5a – Vascular effects( C3a & C5a) – Leukocyte activation, adhesion, chemotaxis(C5a) – Phagocytosis(C3b,iC3b) Page 22

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