1. Chemical Mediators and Regulators of Inflammation 1 Dr. Hiba Wazeer Al Zou’bi

2. Systemic Mediators of Inflammation 2

3. Chemical Mediators of Inflammation Mediators may be produced locally by cells at the site of inflammation, or may be derived from circulating inactive precursors (typically synthesized by the liver) that are activated at the site of inflammation Bind to specific cellular receptors on different target cells, or have direct enzymatic activity. May have limited targets, or wide spread activities May stimulate target cells to release secondary mediators with similar or opposing functions Short lived function Short half-life (AA metabolites) Inactivated by enzymes (kininase on bradykinin) Eliminated (antioxidants on O2 species) Inhibited (complement inhibitory proteins) 3

4. Histamine and Serotonin Among the first mediators released in acute inflammation. Histamine: cause arteriolar dilatation and increase vascular permeability by induce endothelial contraction and formation of interendothelial gap, and inactivated by histaminase. Serotonin (5-hydroxytryptamine): It induces vasoconstriction during clotting. 4

5. Histamines Release of histamine Physical injury Binding of IgE to Fc receptors on mast cells Anaphylatoxins (C3a, C5a) binding Leukocytes derived histamine releasing ptn Neuropeptides (substance P) Cytokines (IL-1, IL-8) 5

6. Arachidonic Acid Metabolism 6 Cell membrane PLA2 AA Cyclooxygenase Lipooxygenase PGE2 PGF2 PGD2 PGI2 TXA2 PAF LTB4 LTC4, D4, E4 Lipoxin A4, B4

7. Generation of AA Metabolites 7

8. Products of the cycloxygenase pathway of AA (Eicosanoids) metabolism TXA2 –Vasoconstriction –Stimulates platelets aggregation PGI2 (Prostacyclin) –Vasodilatation –Inhibits platelets aggregation PGD2, PGE2 –Vasodilatation –Increase vascular permeability –Edema formation –Pain (PGE2) 8

9. Products of the lipoxygenase pathway of AA metabolism LTB4 –Potent chemotactic agent for neutrophil LTC4, LTD4 and LTE4 –Bronchospasm –Increased vascular permeability –Vasoconstriction Lipoxins (LXA4 & LXB4) –Inhibit neutrophil chemotaxis and adhesion 9

10. Platelet-activating Factor Generated from membranes phospholipids by Phospolipase A2 Aggregates and degranulates platelets Bronchoconstriction Potent vasodilator and increased vascular permeability (100 to 1000 times more potent than histamine) Effects on leukocytes –Increase adhesion to endothelial cells –Chemotactic –Leukocytes degranulation –Oxygen burst 10

11. Cytokines Polypeptides produced by many cells. The major cytokines in acute inflammation are: TNF, IL-1, IL-6 Chemoattractant cytokines called chemokines. Cytokines that are more important in chronic inflammation: Interferon-γ (IFN-γ) and IL-12. 11

12. Major Effects of IL-1 & TNF 12

13. Chemokines The main functions of chemokines are to recruit leukocytes to the site of inflammation. Chemokines also activate leukocytes: increased affinity of leukocyte integrins for their ligands on endothelial cells. Chemokines are classified into four groups based on the arrangement of conserved cysteine residues, The two major groups are the CXC and CC chemokines:

14. CXC chemokines, act primarily on neutrophils: IL-8. CC chemokines include: Monocyte chemoattractant protein-1 (MCP- 1), Macrophage inflammatory protein-1α (MIP-1α) Eotaxin (chemotactic for eosinophils).

15. Oxygen derived free radicals At low levels Increase expression of: –Chemokines –Cytokines –Adhesion molecules At high levels Endothelial damage & thrombosis Protease activation & inhibition of antiproteases ( breakdown of the ECM) Direct damage to other cells 15 Protective mechanisms against free radicals include: catalase, superoxide dismutase, and glutathione

16. Nitric Oxide Produced from arginine by the effect of nitric oxide synthase (NOS) Role in inflammation: –Vasodilator (smooth muscle relaxant) –Antagonist of platelets adhesion, aggregation and degranulation –Reduces leukocytes adhesion and recruitment –Microbicidal in activated macrophages 16

17. Nitric Oxide 17

18. Lysosomal constituents Acid proteases generally are active only in the low-pH environment of phagolysosomes Neutral proteases (active in extracellular location): –Elastases, collagenases, and cathepsin –Cleave C3 and C5 producing C3a & C5a –Generate bradykinin like peptides from kininogen. Minimizing the damaging effects of proteases is accomplished by antiproteases present in plasma and tissue fluids: –Alpha 1 antitrypsin (Major inhibitor of neutrophil elastase) –Alpha 2 macroglobulin 18