Chemical mediators of inflammation

1. Chemical Mediators of Inflamation By: Ahsan Shafiq

2. Origin Locally by cells(cell derived mediators) Liver Inactive precursors in plasma(plasma protein derived mediators)

3. Cell derived Mediators Preformed in secretory granules→Vasoactive Amines e.g Histamine, serotonin Newly Synthesized Arachidonic Acid Metabolites(PGS, PGI2, TXA2, LTS, LXS) TNF, IL-1 Cytokines ROS NO Neuropeptides PAF Lysosomal Enzymes of WBCs

4. Plasma Protein Derived mediators Complement System Coagulation & K inin System

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

6. Cell Derived Mediators Serotonin Produced mainly within platelets dense body granules Released during platelet aggregation Cause vasodilatation, Increase vascular permeability

7. Cell Derived Mediators AA Metabolites Cyclooxygenase pathway PGD2,PGE2,PGF2 α 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

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

9. Cell Derived Mediators PAF Produced by WBCs & endothelial cells Causes V.C, Bronchoconstriction

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)

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

12. Cell Derived Mediators Systemic Effects Fever Lethargy Increased sleep Decreased appetite Hepatic synthesis of acute phase proteins Metabolic wasting Corticosteroids Synthesis

13. Cell Derived Mediators Chemokines Helps in recruitment o f Leukocytes Responsible for anatomic distribution of B & T lymphocytes in different areas of lymph nodes & spleen

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)

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 )

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

17. Cell Derived Mediators Neuropeptides ( e.g Substance P) Transmit pain signals Regulate vessel tone & thus vascular permeability

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

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

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

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

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)