Mediators of inflammation

mediator of inflammation

1. Mediators of inflammation 2 Definition: Chemical mediators that are responsible for vascular and cellular events. It may either of two types, Cell Derived - produced locally by cells at the site of inflammation Plasma derived – mainly from liver Some mediators are derived from Necrotic cells

2. Classification 3 Cell derived mediators Plasma derived mediators

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4. 1. Cell derived mediators 5 vasoactive amines (serotonin,histamine) A rachidonic acid metabolites cycloxygenase pathway lipoxygenase pathway Lysosomal components Platelet activating factor Cytokines ( IL-1,TNF-α,TNF-β,IF-γ,Chemokines) f) Nitric oxide and oxygen metabolites

5. a) Vasoactive amines Histamine :- Histamine is an organic nitrogenous compound as well as regulating physiological function in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Mast cells are richest source of histamine , basophiles and platelets. Released by the stimuli of various agents like Heat, Cold, Irradiation, Irritant chemicals, Anaphilatoxins, Interleukins,.. etc. Actions ; Vasodilation Vascular permeability Itching and pain 6

6. Serotonin/5-hydroxy tryptamine :- The scientific name for serotonin is 5-hydroxytryptamine, or 5-HT. It is mainly found in the chromafin cells of GIT, Spleen, Nervous tissue, Mast cells, Platelets. brain, bowels, and blood. Actions ; Similar to Histamine, but less potent Vasodilation Vascular permeability 7

7. b) Arachidonic acid Metabolites Arachidonic acid  is a polyunsaturated fatty  acid   produced by endothelial cells, leukocytes and platelets act locally on smooth muscle, endothelium and platelets origin : Arachidonic acid derived from dietary sources or by conversion from the linoleic acid . And released by activated phospholipases (in injury) two important pathways: cyclooxygenase (COX) lipoxygenase

8. AA Metabolites Cyclooxygenase pathway PGD2,PGE2,PGF2α (prostaglandin) V.D Potentiates Edema formation PGI2 ( prostacyclin ) Produced by prostacyclin synthase in endothelial cell V.D, Inhibits Platelet aggregation TxA2 ( throboxane A2) Produced by Thromboxane synthase in pllatelets stimulates platelets aggregation

9. Cyclooxygenase Pathway

10. Lipoxygenase Pathway : present in neutrophils 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 PAF Platelet - activating factor , or AGEPC (acetyl- glyceryl -ether- phosphorylcholine ), is a potent phospholipid   activator  and mediator of many leukocyte functions, platelet  aggregation Produced by WBCs & endothelial cells Causes V.C, Bronchoconstriction

11. Lipoxygenase Pathway HPETE, hydroperoxyeicosatetraenoic acid. HETE, hydroxyeicosatetraenoic acid;

12. Major effects of interleukin-1 (IL-1) and tumor necrosis factor (TNF) in inflammation

13. c) Lysosomal com p onents 14 Source :- Neutrophiles and monocytes Potent mediators Realease of acid proteases, collagenase, elastase, plasminogen activator   Lysosomes  contain a wide variety of enzymes such as nucleic acids, proteins, and polysaccharides.

14. d) Platelet activating factor Phospholipid derived mediator Released from :- Platelets, basophil, mast cells, neutrophils macrophages, endothelial cells Actions :- Vascular permeability Vasoconstriction Vasodilatation 15 Also known as PAF,  or AGEPC (acetyl- glyceryl -ether- phosphorylcholine ), is a potent  phospholipid  activator and mediator of many  leukocyte  functions,  platelet  aggregation and degranulation ,  inflammation ,

15. e) Cytokines 16 “ Cytokines are proteins produced by many cell types (activated lymphocytes, macrophages, and dendritic cells) .” Cytokines Some mediate communication between WBCs(Interleukins) Some play role in inflammation(TNF, IL-1, Chemokines, IFN-γ , IL-12) mediate and regulate immune and inflammatory reactions

16. Actions :- Adhesion of leucocytes to endothelium S ynthesis of Prostacyclin, which is a vasodilator and anti aggregator of platelets Synthesis of thrombogenic effect on endothelial surface 17

17. f ) Nitric oxide and oxygen metabolites 18 Functions of nitric oxide (NO) in blood vessels and macrophages, produced by two NO synthase enzymes. NO causes vasodilation, and NO free radicals are toxic to microbial and mammalian cells. NOS: nitric oxide synthase.

18. 2.Plasma derived mediators 19 The kinin system : The clotting system : The fibrinolytic system : The complement system :

19. 2: Plasma Protein derived mediators Page 20 Kinin System : The  kinin – kallikrein   system  or simply  kinin system  is a poorly hormonal  system  . It consists of blood proteins that play a role in inflammation, blood pressure control, coagulation and pain. Ultimately leads to formation of bradykinin Bradykinin causes A rteriolar dilation , increases vascular permeability & broncho constriction

20. a) The kinin system factor XII c o n tact factor XIIa prekallikrein activator Plasma prekallikrein kalli k r ein ki n i n o g en B radykinin blood vessels to dilate (enlarge) 21

21. Clotting System : Coagulation , also known as  clotting , is the process by which blood changes from a liquid to a gel, forming a blood  clot 12a → 11a → 10a → 2a (Thrombin) Thrombin converts fibrinogen into fibrin & generates fibrinopeptides Fibrinopeptides → Increased Vascular permeability & chemotactic for WBCs

22. b) Clotting system factor XII c o n tact factor XIIa XI XIa +VIIa +PF3 X Xa +Va +PF3 prothrombin thrombin f ibr i n o f ibr i n o g en f ibr i n Peptides plasmin 23

23. Fibrinolytic System : to remove the clot after the vasculature is repaired, as well as to degrade clots that form in the bloodstream. 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

24. C) Fibrinolytic system 25

25. Mainly leads to the formation of C3a & C5a Vascular effects( C3a & C5a) Leukocyte activation, adhesion, chemotaxis(C5a) Phagocytosis(C3b,iC3b) Complement System: The complement system is a collection of soluble proteins The  complement system  is a part of the immune  system that enhances ( complements ) the ability of antibodies and phagocytic cells to microbes and damaged cells from an organism, promotes inflammation, and attacks the pathogen's plasma membrane Membrane attack complex cause pores in cell of invading microbes.

26. Three pathways : Classical pathway (antibodies) Alternate pathway (microbe LPS) Lectin pathway (sugar on microbes)

27. Interrelationships between the four plasma mediator systems triggered by activation of factor XII (Hageman factor). Note that thrombin induces inflammation by binding to protease-activated receptors (principally PAR-1) on platelets, endothelium, smooth muscle cells, and other cells.