CHEMICAL MEDIATORS OF INFLAMMATION

1. Cairo University Faculty of Veterinary Medicine Department of Pathology CHEMICAL MEDIATORS OF INFLAMMATION تحت اشراف أ.د/ كوكب طالب/ محمد محمود محمد مشالى عبد الحميد رقم/07274

2. Introduction: Inflammation • provoked response to tissue injury • chemical agents • cold, heat • trauma • invasion of microbes • serves to destroy, dilute or wall off the injurious agent • induces repair • protective response • can be potentially harmful

3. CARDINAL SIGNS OF ACUTE INFLAMMATION Heat Redness Swelling Pain Loss of function

4. Inflammation - Mechanism • Vaso dilatation • Exudation - Edema • Emigration of cells • Chemotaxis • Phagocytosis

6. CHEMICAL MEDIATORS OF INFLAMMATION • Exogenous • Endotoxins • Endogenous • Plasma • Leukocytes • Endothelial cells • Fibroblasts Definition: Any messenger that acts on blood vessels, inflammatory cells, or other cells to contribute to an inflammatory response. (Pretty much anything...)

8. Locally produced Histamine Seratonin/5HT Interleukins. Prostaglandins Leukotrienes Plasma derived Kinins Complements Coagulation system Plasminolysis system Others: H2O2, NO Chemical Mediators of Inflammation:

9. CHEMICAL MEDIATORS OF INFLAMMATION Facts • Mechanism of action • Receptor-ligand interactions (1o) • Direct enzymatic activity • Mediate oxidative damage • Extensive network of interacting chemicals • High degree of redundancy • Guarantees amplification and maintenance of inflammatory response • Short t ½ and are harmful

10. CHEMICAL MEDIATORS • Vasodilation • Prostaglandins, Nitric Oxide • Increased Vascular Permeability • Vasoactive amines (histamine, serotonin), C3a and C5a, Bradykinin, Leukotrienes, PAF, • Chemotaxic Leukocyte Activation • C5a, LTB4, Chemokines

11. CHEMICAL MEDIATORS OF INFLAMMATION • Fever • IL-1, IL-6, TNF, Prostaglandins • Pain • Prostaglandins, Bradykinin • Tissue Damage • Neutrophil and Macrophage products • Lysosomal enzymes • Oxygen metabolites • NO Bradykinin

12. VASOACTIVE AMINES • Increase Vascular Permeability and Vascular Permeability • Histamine and Serotonin • Mediators in the immediate active phase of increased permeability • Promotes contraction of smooth muscle • Stimulates to cells to produce eotaxins • Serotonin found in rodent mast cells

13. Vasoactive Amines Continued • Releasing Stimulators • Direct physical or chemical injury • Binding of IgE- Ag- complexes • Fragments of C3a and C5a • Histamine releasing factors (pmn’s and θ) • Cytokines (IL-1, IL-8) • Neuropeptides

14. Kinin system Highly vasoactive Complement system Vasoactive Chemotactic Clotting system Vasoactive Cleaves C3 PLASMA PROTEASES 3 interrelated systems are active within this category

15. Interaction of Kinin-, Coagulation- and Complement system during acute inflammation Factor XII (Hageman) Collagen, basement membrane, platelets and microbial surfaces XIIa Kinin cascade Clotting cascade Intrinsic pathway Prekallikrein Kallikrein Acute Inflammation PAR* Prothrombin Thrombin Bradykinin HMWK Fibrinolysis Plasminogen Plasmin Fibrin Fibrinogen Complement * Protease activated receptors C3a C3

16. COMPLEMENT SYSTEM • Plasma proteins - act against microbial agents • Products of activated complement • Vascular permeability • Chemotaxis • Opsonization • Lysis

17. COMPLEMENT SYSTEM Few reminders • Classical pathway • Alternate pathway • Common pathway • Important inflammatory mediators • C3a and C5a (anaphylatoxins) • Cause release of histamine from mast cells • Lysosomal enzyme release in inflammatory cells • C5a • Activates lipoxygenase pathway • Chemotactic many inflammatory cells • Increases adhesion of leukocytes

18. COMPLEMENT SYSTEM And Inflammation • C5b-9 membrane attack complex • Lyses cells • Stimulates arachidonic acid metabolism • Produces reactive oxygen metabolites

19. Complement Cascade

20. KININ SYSTEM BRADYKININ • Activated by Hageman factor (XIIa) • Bradykinin • Release of vasoactive nonapeptide bradykinin • Generated from the plasma • Potent vasodilator • Increased vascular permeability • Contraction of smooth muscle • Produce pain • Stimulates release of histamine • Activates the arachidonic acid cascade

22. COAGULATION SYSTEM Clotting system • Plasma proteins • Can be activated by Hageman factor • Thrombin converts fibrinogen to fibrin • Fibrinopeptides are formed • ↑vascular permeability • Chemotactic for leucocytes • Plasmin is important in lysing fibrin clots, • Activates Hageman factor (XII) ⇨ bradykinin • Cleaves C3 ⇨ C3a • "fibrin-split products" formed from fibrin breakdown • ↑ vascular permeability

23. COAGULATION CASCADE TF: tissue factor; HK: high-molecular-weight kininogen; PK: prekallikrein; PL: phospholipid; PT: prothrombin; TH: thrombin.

24. Clotting System

25. HAGEMAN FACTOR Dependent Factors • Factor XII of intrinsic coagulation cascade • Activated by • Negatively charged surfaces • Platelets • Proteases from inflammatory cells • Causes • Coagulation • Activation of fibrinolytic system • Produces bradykinin • Activates complement • Provides an amplification system

26. IMPORTANT NOTE • Activated Hageman factor (factor XIIA) initiates the clotting, fibrinolytic and kinin systems. The products of this initiation (kallikrein, factor XIIA, and plasmin, but particularly, kallikrein) can, by feedback, activate Hageman factor, resulting in significant amplification of the effects of the initial stimulus.

28. CYTOKINES • Transmitters for cell-to-cell chatting • Modulate cell function • Primarily from activated macrophages and lymphocytes • IL-1, IL-8, TNF

29. IL-I and TNF “Master Cytokines” • Origin • Monocytes • Macrophages • Similar in action • Endothelium • Acute phase proteins • Fibroblasts

30. Other Cytokines Chemokines??? • IL-5 • Eosinophils • IL-6 • B and T cells • IL-8 • Neutrophils • Lesser degree monocytes and eosinophils

32. GROWTH FACTORS • Platelet derived growth factor • Transforming growth factor β • Chemokines - Leukocytes and Mesenchymal Cells • Important in regeneration and repair

33. NITRIC OXIDE (NO) Just say NO! • Nitric oxide is synthesized from L-arginine • 2 enzymes and many factors produce NO • 3 effects • ♥♥ physical mediator of vascular tone • Host defense (forms perroxynitrite) • Signaling molecule – especially brain • Reduces platelet aggregation and adhesion • Inhibits several features of mast cell induced inflammation • Uncontrolled NO production • Can lead to massive peripheral -Vasodilation -Shock

36. LYSOSOMAL CONSTITUENTS • Neutrophils, Monocyte/Macrophages • Enzymes and proteins within granules • Cationic proteins • ↑ vascular permeability • Chemotactic • Neutral proteases • Degrade ECM

37. OXYGEN-DERIVED FREE RADICALS • Cause endothelial damage • Protein destruction by inhibiting antiproteases • Injury to variety of cells • Don’t forget the antioxidants • Ceruloplasmin • Transferrin • Superoxide dismutase • Catalase • Glutathione peroxidase