Chemical mediators of inflammation

chemical mediators of inflammation

1. CHEMICAL MEDIATORS OF INFLAMMATION Aiswarya T homas APSC Pariyaram

2. CHEMICAL MEDIATORS OF INFLAMMATION Also called as permeability factors or endogenous mediators of increased vascular permeability Large and increasing number of endogenous compounds which can enhance vascular permeability Chemical mediators are released from cells, plasma, or damaged tissue

3. CELL DERIVED MEDIATORS Vasoactive amines (Histamine, 5-hydroxy tryptamine, neuropeptides ) Arachidonic acid metabolites (Eicosanoids) Metabolites via cyclo-oxygenase pathway (prostaglandins, thromboxane A2,prostacyclin,resolvins) Metabolites via lipo-oxygenase pathway (5-HETE,leukotrienes,lipoxins) Lysosomal components (from PMNs ,macrophages) Platelet activating factor Cytokines(IL-1,TNF- α ,TNF- β ,Chemokines ) Free radicals (oxygen metabolites ,nitric oxide)

4. 2. PLASMA DERIVED MEDIATORS Products of The kinin system The clotting system The fibinolytic system The complement system

5. CELL DERIVED MEDIATORS 1. VASOACTIVE AMINES ¡) Histamine Stored in the granules of mast cells, basophils and platelets. Main actions Vasodialation, incresed vascular permeability, itching, pain ¡¡) 5-Hydroxytryptamine Present in tissues like chromaffin cells of GIT, spleen, nervous tissue, mast cells and platelets.

6. ¡¡¡)Neuropeptides Produced in the central and peripheral nervous systems. Main actions ¡) Increased vascular permeability ¡¡) Trasmission of pain stimuli ¡¡¡) Mast cell degranulation

7. 2. ARACHIDONIC ACID METABOLITES (EICOSANOIDS) Arachidonic acid (fatty acid) is released from the cell membrane by phospholipases. It is then activated to form arachidonic acid metabolites or eicosanoids by one of the following two pathways: cyclo - oxygenase and lipo – oxygenase pathway

8. Metabolites via cyclo oxygenase pathway Activated arachidonic acid Cyclo-oxygenase PGG2 PGH2 + Free oxygen radical PGD2,PGE2 Vasodilator Bronchodilator ↑ permeability PGF2- α Vasodilator bronchoconstictor TXA2 Vasoconstictor Bronchoconstrictor Platelet aggregation PGI2 Vasodilator Bronchodilator Anti-aggregating agent RESOLVINS Inhibitor of pro-inflammatory cytokines

9. Metabolites via lipo oxygenase pathway Activated arachidonic acid Lipo -oxygenase 5-HPETE 5-HETE LTA4 LTB4 Chemotactic Cell adherence LTC4 LTD4 LTE4 LIPOXINS Smooth muscle constrictor Vasoconstrictor Bronchoconstrictor ↑Vascular permeability

10. 3. LYSOSOMAL COMPONENTS The inflammatory cells neutrophils and monocytes contain lysosomal granules which on release elaborate a variety of mediators. ¡) Granules of monocytes and tissue macrophages On degranulation these cells release acid proteases, collagenase , elastase and plasminogen activator

11. ¡¡)Granules of neutrophils PRIMARY SECONDAR Y TERTIARY Contain myeloperoxidase, acid hydrolases, acid phosphatase, phospholipase, elastase and protease. Contain Alkaline phosphatase, gelatinase, collagenase, lysozyme, vitamin b12, binding proteins Contain Gelatinase and acid hydrolase .

12. 4. PLATELET ACTIVATING FACTOR (PAF) Released from IgE sensitised basophils or mast cells, leucocytes, endothelium and platelets. ACTIONS Increased vascular permeability Vasodialation and vasoconstiction Bronchoconstriction Adhesion of leucocytes to endothelium Chemotaxis

13. 5. CYTOKINES These are polypeptide substances produced by activated lymphocytes (lymphokines) and activated monocytes (monokines) Major cytokines- interleukin-1(IL-1), tumour necrosis factor (TNF) α and β , Chemokines. ACTIONS IL-1 and TNF- α , TNF- β Induce endothelial effects- Increased leucocyte adherece Thrombogenicity Fibroblastic proliferation

14. IFN-Y Activation of macrophages and neutrophils Synthesis of nitric acid synthase Chemokines IL-8 Chemotactic for neutrophils Eotaxin chemotactic for eosinophil

15. 6. FREE RADICALS:OXYGEN METABOLITES AND NITRIC OXIDE . ¡)Oxygen derived metabolites Released from activated neutrophils and macrophages . ACTIONS Endothelial cell damage and there by increased vascular permeability Activation of protease and inactivation of antiprotease causing tissue matrix damage

16. ¡¡)Nitric oxide (NO) Formed by activated macrophages ACTIONS Vasodialation Anti-platelet activating agent

17. 2. PLASMA DERIVED MEDIATORS These include the various products derived from activation and interaction of 4 interlinked systems: kinin, clotting, fibinolytic and complement. Hageman factor(factor xii) of clotting system plays a key role in interactions of the 4 systems. Activation of factor xii in vivo by contact with basement membrane and bacterial endotoxins, and in vitro with glass or kaolin leads to activation of clotting, fibrinolytic, and kinin systems. The end products of the activated clotting, fibrinolytic and kinin system activate the complement system.

18. Factor XII contact Factor XII a FIBRINOLYTIC SYSTEM CLOTTING SYSTEM KININ SYSTEM Plasminogen Prothrombin Plasma prekallikrein prekallikrein Plasminogen activator activator Thrombin Kallikrein Plasmin Fibrin Kininogen Fibrin split products Bradykinin COMPLEMENT SYSTEM Permeability factors (C3a, C5a), MAC (C5b,C9)

19. BRADYKININ ACTIONS Smooth muscle contraction Vasodilation Increased vascular permeability Pain FIBRINOPEPTIDES Increased vascular permeability Chemotaxis Anticoagulant activity

20. THE COMPLEMENT SYSTEM The activation of complement systemcan occur by: Classic pathway via non immunological agents Alternate pathway via non immunological agents Complement system on activation yields activated products – anaphylotoxins (C3a, C4a, C5a) and membrane attack complex (MAC) – C5b, C6, C7…. ACTIONS C3a, C5a,C4a activate mast cells and basophils C3b is an opsonin C5a is chemotactic for leucocytes