Chemical mediators of inflammation.pptx

pathology inflammation

1. Chemical mediators of inflammatio n Dr Mustafa Ali

2. Inflammation Inflammation is a complex reaction to injurious agents such as microbes and damaged , usually necrotic, cells that consists of vascular responses, migration and activation of leukocytes, and systemic reactions. fundamentally a “ protective response ”

3. Inflammation The Inflammatory response consists of two main components, a vascular reaction and a cellular reaction. The vascular and cellular reactions of both acute and chronic inflammation are mediated by chemical factors that are derived from plasma proteins or cells and are produced in response to or activated by inflammatory stimulus.

4. Chemical mediators of inflammation Classified on basis of origin Cell derived mediators : sequestered in intracellular granules: 1. Histamine 2. Serotonin 3. Lysosomal enzymes synthesized de novo : Prostaglandins

5. Chemical mediators of inflammation 2. Leukotrienes 3. Platelet-activating factors 4. Activated oxygen species 5. Nitric oxide 6. Cytokine

6. Chemical mediators of inflammation Plasma derived mediators : 1. Kinin system 2. Clotting system 3. Complement system

7. Chemical mediators of inflammation

8. Cell derived mediators

9. HISTAMINE It is a vasoactive amine, widely distributed in tissues Source: Mast cells Basophils Platelets Actions: vasodilatation and increased vascular permeability Contraction of non vascular smooth muscles(bronchi)

10. HISTAMINE Stimulate cells to produce eotaxins (attract eosinophils) Endothelial cells contraction and widening of gaps Releasing stimulators: direct physical and chemical injury Binding of IgE-Ag complex

11. HISTAMINE Anaphylatotoxins ( C3a and C5a ) Neuropeptides ( substance-P ) Cytokines ( IL-1 and IL-8 )

12. Endothelial cell contraction

13. SEROTONIN another vasoactive amine , with actions similar to histamine Source: Platelets Releasing stimulators: Collagen Thrombin ADP Ag-Ab complex

14. PROSTAGLANDINS & LEUKOTRIENES These are arachidonic acid metabolites, also called “ eicosanoids” Synthesized by two major classes of enzymes: Cyclooxygenases (prostaglandins and thromboxanes ) Lipooxygenases (leukotrienes and lipoxins)

15. PROSTAGLANDINS & LEUKOTRIENES Source: All leukocytes Platelets Endothelial cells Actions: Prostaglandins : prostacyclin PGI2: - Vasodilatation - Inhibit platelet aggregation

16. PROSTAGLANDINS & LEUKOTRIENES Thromboxane A2: - Vasoconstriction - promote platelet aggregation PGD2 ,PGE2 and PGF2: -Vasodilatation -potentiate edema - increases pain

17. PROSTAGLANDINS & LEUKOTRIENES Leukotrienes: - vasoconstriction - bronchospasm - increased permeability Lipoxins: - vasodilatation -inhibit neutrophil chemotaxis -stimulate monocyte adhesion

18. PROSTAGLANDINS & LEUKOTRIENES

19. PLATELET- ACTIVATING FACTOR Another phospholipid derived mediator Produced by leukocytes , platelets , endothelial cells and macrophages/ monocytes. Actions:- vasoconstriction and bronchoconstriction

20. CYTOKINES Transmitters for cell to cell chatting , thus modulate cell function Source: activated lymphocytes and macrophages Examples:- TNF and IL1 Stimulated by endotoxins , microbial product , and inflammatory stimuli Induces acute phase responses associated with infection or injury.

21. CYTOKINES

22. Oxygen derived free radicals INCLUDE–hydrogen peroxide (H2O2), superoxide anion (O2-) and hydroxyl radicals (OH●) Cause - endothelial damage and increased vascular permeability Inhibit antiproteases –damage to ECM The antioxidants - Superoxide dismutase - glutathion peroxidase - synergistic vitamins

23. Plasma derived mediators

24. PLASMA PROTEASES Consists of 3 systems that are interrelated 1.Complement system a) Killing system b) Vasoactive c) Chemotactic 2.Kinin system a) Highly vasoactive 3.Clotting system a) Vasoactive b) Cleaves C3

25. Interaction between plasma mediator systems

26. Complement system Three pathways: 1 •Classical pathway (antibodies) 2 •Alternate pathway(microbes) 3 •Lectin pathway (sugar on microbes) Important functions: - Release histamine = Increased Vascular permeability - Opsonize microorganisms to help with phagocytosis - Membrane Attack Complex (MAC) –Lysis of pathogens

27. Complement cascade

28. KININ SYSTEM •Activated by Hageman factor (XIIa) •Bradykinin –Potent vasodilator –Contraction of smooth muscle –Produces pain –Stimulates release of histamine

29. KININ SYSTEM

30. COAGULATION SYSTEM –Intrinsic pathway -Hageman factor(XII) –Extrinsic pathway Activation of thrombin Thrombin converts fibrinogen to fibrin Thrombin –also links clotting system to inflammation by acting on PAR-1.

31. COAGULATION SYSTEM

32. SUMMARY Vasodilatation, an early event in inflammation is caused by histamine , PGs and NO. Increased vascular permeability is caused by histamine , anaphyllotoxins(C3a , C5a ) ,kinins , LTs ,PAF and Substance-P . Chemotaxis is caused by C5a , LTB4 , and chemokines

33. SUMMARY PGs causes vasodilatation , pain , fever and potentiate edema. IL-1 and TNF are critical for endothelial-leukocyte interaction and produce acute phase reactants. Oxygen free radicals chiefly cause tissue destruction.

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