Inflammatory mediators- Pharmacology

Definition: Any messenger that acts on blood vessels, inflammatory cells, or other cells to contribute to an inflammatory response.
Cell derived mediators


Plasma derived mediators
vasoactive amines (serotonin,histamine)
arachidonic 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
Histamine :-
Stored in granuls of mast cells, 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

1. INFLLAMATORY MEDIATORS BY;- SANCHIT DHANKHAR 1

2. Mediators of inflammation Definition: Any messenger that acts on blood vessels, inflammatory cells, or other cells to contribute to an inflammatory response. 2 2

3. Classification 3 3 Cell derived mediators Plasma derived mediators

4. 4 4

5. 1. Cell derived mediators 5 5 v asoac t i v e ami n es ( se r o t o n i n ,his t a m i n e) arachidonic acid metabolites c y cl o x yg enase pat h w a y lipoxygenase pathway Lysosomal components P la t elet act i v ating fac t or Cytokines ( IL-1,TNF-α,TNF-β,IF-γ,Chemokines) f) Nitric oxide and oxygen metabolites

6. a) Vasoactive amines 6 Histamine :- Stored in granuls of mast cells, basophiles and platelets. Released by the stimuli of various agents like Heat, Cold, Irradiation, Irritant chemicals, Anaphilatoxins, Interleukins,.. etc. Actions ; Vasodilation V ascular permeab i lity Itching and pain 6

7. Serotonin/5-hydroxy tryptamine :- Present in chromafin cells of GIT, Spleen, Nervous tissue, Mast cells, Platelets. Actions ; Similar to Histamine, but less potent Vasodilation V ascular p e rmeab i lity 7 7

8. b) Arachidonic acid Metabolites Lipoxygenase pathway Cyclo-oxygenase pathway 8 8

9. Cell membrane phospholipids 9 Stimulus (phospholipase) (Inhibition by st ero i ds) Arachidonic Chemotactic lipids O 2 - 5 Li p oxi g ena s e ac i d O 2 O 2 Cyclooxigenase (inhibitable w/ aspirin, indomethacin) 5HPE T E LTA 4 LTC 4 LT D 4 LTE 4 5 HE T E Chemotaxis LTB 4 Chemotaxis Vasoconstriction Bronchoconstricti o n ↑Vascular permeability 2 2 x PG G PG H + [O ] pero x idase sin t e t as e sin t e t as e Inhibits Pro st a cyclin PGI2 thrombocyte aggr. Vasodilatation Enhances oedema formation Thro m bo x ane A 2 Vasoconstrictio n Isomerase Thro m bocyte aggregation Reductase PG E PGD 2 PGF2 α Vasodilatation Oedema formation Che mot a ctic lipids

10. c) Lysosomal comonents 10 10 Sou r c e : - N eu t r o p hiles and mon o c y t es Potent mediators Degredation of bacterial and extracellular components Chemotaxis Realease of acid proteases, collagenase, elastase, plasminogen activator

11. d) Platelet activating factor 11 Phospholipid derived mediator Released from :- Platelets, basophil, mast cells, neutrophils macrophages, endothelial cells Actions :- V ascular p e rmeab i lity Vasoconstriction Vasodilatation Bronchoconstriction Adhesion of leukocytes to endothelium Chemotaxis, degranulation

12. e) Cytokines 12 “Cytokines are a diverse group of small protein molecules with potent biological activity whose main function is in the regulation of immune responses.” Main Cytokines are :- Interleukins Interferons T u m or nec r os i s fac t or Chemokines Transforming growth factor-beta Adipokines- leptin & adiponectin

13. Actions :- Adhesion of leucocytes to endothelium Synthesis of Prostacyclin, which is a vasodilator and anti agg r ega t or of pl a t elets S y n the s i s of P A F and th r ombo g enic ef f ect on endothelial surface 13

14. f) Nitric oxide and oxygen metabolites 14 Endothelium derived relaxing factor Macrophages, endothelial cells, neurons Actions :- Vasodilation Anti-platelet activating agent Microbicidal action H 2 O 2 , Superoxide, Toxic NO products produced by activated neutrophiles and microphages Actions :- E n d o th elial c ell dam a g e, t i ssue dam a g e and v ascular permeability

15. 2.Plasma derived mediators 15 The kinin system The clotting system The fibrinolytic system Th e c om p lement s y s t em

16. 4 interlinked systems H a g eman fac t or( f ac t or X II) End product of clotting ,fibrinolytic ,kinin system will act i v a t e c omplement s y s t em. 16

17. a) The kinin system 17 fac t or X II c o n tact fac t or X I I a prekallikrein activator Plasma prekallikrein kalli k r ein ki n i n o g en bradykinin

18. Actions :- Smooth m u scle c o n t r action Vasodilation v ascular permeab i lity pain 18

19. b) Clotting system 19 fac t or XII c o n tact factor XIIa XI XIa +VIIa +PF3 X X a + V a + P F3 prothrombin thrombin f ibr i n o f ibr i n o g en f ibr i n Peptides plasmin

20. Actions :- Inc r ease v ascular permeab i lity Chemotaxis for leucocytes Anti c oa g ulan t act i vity 20

21. C) Fibrinolytic system 21

22. Actions :- Activation of factor XII to form prekallikrein activator that stimulates kinin system to generate bradykinin Spl i t s o f f c om p lement c 3 t o f o r m c3a, w hich is permeability factor Degrades fibrin to split products, they increase v ascular permeab i lity 22

23. D) Complement system 23 P r oduct of c omplement s y s t em i s ana p h y la t o xi n s c3a and c5a. Potency is c3a>c5a>c4a A ctio n s : - r elease histamine f r om mas t c ells and basophils C5a is chemotactic for leucocytes. Membrane attack complex cause pores in cell of invading microbes.

24. Inflammatory mediators and their function I. 24 Mediators Function Histamine, serotonin, bradykinin, C3a, C5a, PGD 2 , PGE 2 , PGI2, LTC 4 , active Hageman factor, fibrinopeptids Increase the permeability of small vessel FMLP, C5a, TXA 2 , LTB 4 , LTC 4 , LTD 4 , LTE 4 Vasoconstriction Hisztamin, szerotonin, bradykinin, C3a, C5a, TXA 2 , LTB 4 , LTC 4 , LTD 4 , LTE 4 , PAF Smooth muscle contraction C3a, C5a, MCP-1, IL-8 Degranulation of mast and basophil cells LPS, LTD 4 , IL-1, TNF-α, MCP-1 Increased endothel cell cohesion Bradykinin, PGE 2 Pain IL-1, IL-6, TNF-α, MIP-1, PGE 2 Pirogenes TXA 2 , PAF Thrombocyte aggregation

25. Mediators Function FMLP, C5a, IL-8 and other chemokins, LTB 4, PAF, laminin, kollagene fragments, fibrinopeptids, C3b, iC3b, IgG (Fc rész), fibronectin, C 5 a, P A F , TN F - α , I L -8, most chemoattractant, phagocytic materials -phagocytes -chemotaxis -cohesion and phagocytosis -reactive, intermedier O 2 formation and release of lysosomal granules Serum am y loid A (SA A ), C R P , fibrinogene, α 1 -antitripsin, haptoglobin, ceruloplasmin, stb. Acute phase proteins TNF-α, TNF-β, PAF, reactive O 2 intermediers (ROI), reactive N 2 intermediers (RNI), lysosomal enzymes Possible injury of mast cells and tissues bFGF, GM-CSF, TGF- β, TGF- α, IGF-1, PDGF, VEGF/VPF, IL-1, IL-6, IL-8, TNF-α, interferons Angiogenezis Inflammatory mediators and their function II. 25

26. - C-1 inhibitor -  -2 macroglobulin - Antithrombin - III -  -1 protease inhibitor 26

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28. THANKYOU 28