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

5. Chemical Mediators of Inflammation Cell-Derived Plasma- Protein- Derived

6. Chemical Mediators of Inflammation Cell-Derived Vasoactive Amines Eicosanoids PAF Cytokines Chemokines ROS NO Lysosomal Enzymes of Leukocytes Neuropeptides Plasma-Protein- Derived

7. Chemical Mediators of Inflammation Cell-Derived Plasma-Protein- Derived Complement Coagulation and Kinin Systems

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: 1.Physical injury 2.Immune reactions 3.C3a and C5a fragments of complement (anaphylatoxins) 4.Leukocyte-derived histamine-releasing proteins 5.Neuropeptides (e.g. substance P) 6.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 = Arachidonic Acid (AA) Metabolites = Prostaglandins (PG), Leukotrienes, and Lipoxins

15. Eicosanoids May be thought of as hormones but they differ from hormones by: 1.Produced in all tissues rather than in specialized glands 2.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: 1.Cyclooxygenase  Prostaglandins & Thromboxanes 2.Lipooxygenase  Leukotrienes and Lipoxins

20. Chemical Mediators of Inflammation Cell-Derived Vasoactive Amines Eicosanoids PAF Cytokines Chemokines ROS NO Lysosomal Enzymes of Leukocytes Neuropeptides Plasma-Protein- Derived

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 A 2 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: 1.Leukocyte recruitment & activation in inflammation 2.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): 1.Type I (nNOS) : neuronal, not significant in inflammation 2.Type II (iNOS): inducible, in macrophages and endothelial cells, NO production in inflammation 3.Type III (eNOS): constitutive, endothelium

31. NO Functions: 1.Vasodilation 2.Antagonism of platelet activation (adhesion, aggregation, & degranulation) 3.Reduction of leukocyte recruitment 4.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. α 1 -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

35. Chemical Mediators of Inflammation Cell-Derived Vasoactive Amines Eicosanoids PAF Cytokines Chemokines ROS NO Lysosomal Enzymes of Leukocytes Neuropeptides Plasma-Protein- Derived

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