The Cell-Derived Mediators of Chemical Mediators of Inflammation

1. The Cell-Derived Mediators of Chemical Mediators of Inflammation Presented by Sara M. Al-Shaker Wed. 5/11/2008 King Saud University Riyadh, KSA

2. Introduction • What are mediators? A mediator is a substance or structure that mediates a specific response in a bodily tissue

3. General Properties of Chemical Mediators of Inflammation • Site of production Local or remote • Method of action • Mostly by binding to receptors • May have direct enzymatic and/or toxic effects

4. General Properties of Chemical Mediators of Inflammation • Some mediators Stimulate release of secondary effector molecules • Actions of most mediators are tightly regulated Decay Enzymatic inactivation Elimination Inhibition

8. Cell-Derived Mediators • Producing cells: • Tissue macrophages • Mast cells • Endothelial cells • Leukocytes

9. Vasoactive Amines Histamine & Serotonin

10. Vasoactive Amines • Among first mediators in acute inflammatory reactions • Preformed mediators in secretory granules

11. Histamine • Source: many cell types, esp. mast cells, circulating basophils, and platelets • Actions: • ARTERIOLAR DILATION • INCREASED VASCULAR PERMEABILITY • ENDOTHELIAL ACTIVATION • Inactivated by: Histaminase

12. Histamine • Stimuli of Release: • Physical injury • Immune reactions • C3a and C5a fragments of complement (anaphylatoxins) • Leukocyte-derived histamine-releasing proteins • Neuropeptides (e.g. substance P) • Certain Cytokines (e.g. IL-1 and IL-8)

13. Serotonin(5-HT) • Source: Platelets • Action: Similar to histamine’s • Stimulus: Platelet aggregation

14. Eicosanoids Eicosanoids = Arachidonic Acid (AA) Metabolites = Prostaglandins (PG), Leukotrienes, and Lipoxins

15. Eicosanoids • May be thought of as hormones but they differ from hormones by: • Produced in all tissues rather than in specialized glands • Act locally rather than after transport in blood to distant sites • Decay spontaneously OR enzymatically • Have short half-life

16. Eicosanoids • Source: Leukocytes Mast cells Endothelial cells Platelets

17. Arachidonic Acid • 20-carbon polyunsaturated fatty acid (4 double bonds) • Obtained from dietary linoleic acid • Present in the body in its esterified form as a component of cell membrane phospholipids • Released from phospholipids via phospholipases

18. AA Metabolism • Two major enzymatic pathways: • Cyclooxygenase  Prostaglandins & Thromboxanes • Lipooxygenase  Leukotrienes and Lipoxins

21. Platelet Activating Factor(PAF) • Another phospholipid derivative • Very potent bioactive molecule • Source: membranes of Neutrophils, monocytes, basophils, endothelial cells, & platelets • Derived by the action of Phospholipase A2 • Acts via G-protein-coupled receptor

22. PAF • Actions: • Platelet activation (aggregation & degranulation) • Vasoconstriction • Bronchoconstriction • Leukocyte adhesion • Leukocyte degranulation • Chemotaxis • Synthesis of other mediators, esp. Eicosanoids

23. Cytokines • Polypeptides • Actions: • Involved in early immune and inflammatory reactions • Some stimulate bone marrow precursors to produce more leukocytes

24. Cytokines • Interleukins (IL) • Tumor Necrosis Factor (TNF) • Chemokines • Interferon-γ (INF- γ) Acute inflammation: IL-1, TNF, & chemokines Chronic Inflammation: INF- γ & IL-12

25. TNF and IL-1 • Source: Activated macrophages Mast cells Endothelial cells • Stimulation: Bacterial endotoxins Immune complexes Products of T-lymphocytes (adaptive immune response)

26. TNF and IL-1 • Actions: Endothelial Activation Both: 1. Stimulate expression of molec. on endothelial cells  2. Increased leukocyte binding and recruitment 3. Enhanced production of additional cytokines (notably chemokines) and eicosanoids

27. TNF and IL-1 • Actions: TNF : • Thrombogenicity of endothelium • Neutrophil activation IL-1: • Tissue fibroblasts activation  increased ECM N.B. TNF and IL-1 may enter the circulation and induce systemic acute-phase reaction

28. Chemokines • Small proteins • They are chemoattractants for leukocytes • Main functions: • Leukocyte recruitment & activation in inflammation • Normal anatomic organization of cells in lymphoid and other tissues • Act via G-protein-coupled receptors (e.g. CXCR4 and CCR5 important for HIV entry into lymphocytes)

29. Reactive Oxygen Species • Synthesized via NADPH oxidase pathway • Source: Neutrophils and Macrophages • Stimuli of release: Microbes Immune complexes Cytokines

30. Nitric Oxide • Short-lived • SOLUBLE • Free-radical gas • Isoforms of NO Synthase (NOS): • Type I (nNOS) : neuronal, not significant in inflammation • Type II (iNOS): inducible, in macrophages and endothelial cells, NO production in inflammation • Type III (eNOS): constitutive, endothelium

31. NO • Functions: • Vasodilation • Antagonism of platelet activation (adhesion, aggregation, & degranulation) • Reduction of leukocyte recruitment • Microbicidial (cytotoxic) agent (with or without ROS) in activated macrophages

33. Lysosomal Enzymes of Leukocytes Leukocytes: Neutrophils & Monocytes Enzymes: • Acid proteases • Neutral proteases (e.g. elastase, collagenase, & cathepsin) Their action is checked by: Serum antiproteases (e.g. α1-antitrypsin)

34. Neuropeptides • Small proteins • Secreted by nerve fibers mainly in lung & GIT • Initiate inflammatory response • Substance P : • Transmits pain signals • Regulates vessel tone • Modulates vascular permeability

36. THANKS!Have a nice day &a GREAT weekend!