Chemical Mediators of Inflammation PDF

Chemical Mediators of Inflammation MEDIATORS OF INFLAMMATION The mediators of inflammation are the substances that initiate and regulate inflammatory reactions. Mediators Of Inflammation They are produced: 1-locally by the cells at the site of inflammation 2- From circulating inactive precursors (ty...

Chemical Mediators of Inflammation MEDIATORS OF INFLAMMATION The mediators of inflammation are the substances that initiate and regulate inflammatory reactions. Mediators Of Inflammation They are produced: 1-locally by the cells at the site of inflammation 2- From circulating inactive precursors (typically produces by liver) which are activated at the site of inflammation. They are of 2 types: 1-Cell-derived mediators 2- Plasma protein –derived mediators O Active mediators are produced only in response to various molecules that stimulate inflammation, including microbial products and substances released from necrotic cells.  most mediators act by binding to specific receptors on different target cells  only one target cell or many types  they may have different actions, different outcomes  direct enzymatic or toxic activities that do not require binding to specific receptors (e.g lysosomal protease,ROS) The actions of mediator are tightly regulated and short lived:  inactivated by enzymes(e.g kininase inactivates bradykinin)  eliminated (antioxidants scavenge toxic oxygen mediators)  inhibited (complement regulatory proteins block complement activation) 1-Cell-derived mediators:  Tissue macrophage , mast cells , endothelial cells  Sequestrated in intracellular granules  Rapidly secreted upon cellular activation(e.g histamine in mast cells)  Synthesized de novo in response to stimuli(prostaglandins and cytokines produced by leukocytes and other cells) Vasoactive amines: 1-Histamine:  vasodilation  Increase vascular permeability  released by mast cells, basophils, platelets in response to: - injury (trauma, heat) - immune reactions (IgE) - anaphylatoxins (C3a, C5a fragments) - cytokines (IL-1, IL-8) - neuropeptides - leukocyte-derived histamine-releasing peptides 2-Serotonin(5-hydroxytryptamine):  vasodilatory effects  platelet dense-body granules  release triggered by platelet aggregation Arachidonic acid metabolites (eicosanoids):  Prostaglandins  Leukotrienes  Lipoxins  AA metabolism →2 major enzymatic pathways: 1-Cyclooxygenase→ prostaglandins and thromboxanes 2-Lipoxygenase→leukotrienes and lipoxins Prostaglandins and thromboxane:  Include:PGD2,PGF20,PGI2(prostacyclin) and thromboxane A2(TXA2)  cyclooxygenase pathway  cause vasodilation and prolong edema  Pain and fever  Cyclooxygenase (COX) blocked by aspirin and NSAIDS. Leukotrienes:  5-lipoxygenase pathway (the major A A- metabolizing enzyme in neutrophils) →LTA4→LTB4andLTC4  Chemotaxins (LTB4)  vasoconstrictors  increased vascular permeability(LTC4,LTD4,LTE4)  bronchospasm(LTC4,LTD4,LTE4)(mast cells) Lipoxins:  Produced by neutrophils and platelets  once in tissues neutrophils change major lipoxygenase derived AA products from leukotriene to anti inflammatory mediators called lipoxins which:  Inhibit neutrophils chemotaxis and adhesion to endothelium  PAF (platelet activating factor)  Derived also from cell membrane phospholipid by the action of phospholipase A  causes :  Vasodilation  increased vascular permeability  Bronchoconstriction  increases leukocyte adhesion (integrin conformation)  Cytokines:  Proteins, cell products that act as a message to other cells, telling them how to behave.  Polypeptides  Products of many cells  Mediators of inflammation and immune response  Molecularly characterized cytokines→ interleukins  IL-1, TNF- and -,IL-6 and chemokins are especially important in acute inflammation.  IL-1 and TNF→ endothelial activation  In chronic inflammation→ IFN-,IL-12  IL-17 (produced by T lymphocytes) →recruit neutrophils  They also enter circulation→ induce systemic acute phase reaction:  Fever  Lethargy  Hepatic synthesis of acute phase proteins (IL-6)  Metabolic wasting (cachexia)  Fall in blood pressure chemokines: Proteins Act as chemo attractants Activate leukocytes They are divided into 1-CXC (e.g IL-8) 2-CC(monocyte chemo attractant protein -1 (MCP-1) and macrophage inflammatory protein1alpha (MIP-1alpha))  Tow of chemokines receptors are CXCR4 and CCR5 Reactive Oxygen Species:  Injure tissues through: Endothelial damage Protease activation Direct injury to cells Antioxidant protective mechanisms: o Catalase o Superoxide dismutase o Glutathione  Nitric Oxide  short-acting soluble free-radical gas with many functions  Produced by endothelial cells, macrophages  causes:    Vascular smooth muscle relaxation and vasodilation Kills microbes in activated macrophages Counteracts platelet adhesion, aggregation, and degranulation  Lysosomal enzymes of leukocytes :  Leak from PMNs and macrophages  Acid proteases (only active within lysosomes)  Neutral proteases such as elastase and collagenase and cathepsin are destructive in ECM  Counteracted by serum and ECM antiproteases→ o Alpha -1 antitrypsin o Alpha-2 macroglobulin  Neuropeptides: o Small proteins (substance p) Transmit pain signal Regular vessels tone Increase vascular permeability 2-Plasma protein –derived mediators complement proteins , kinins circulate in an inactive form undergo proteolytic cleavage to acquire their biologic activity.  Plasma proteases  Complement  Clotting system  Kinins COMPLEMENT PATHWAY:  Components C1-C9 present in inactive form  Activated via 1-classic (C1) pathway 2- alternative (C3) pathway  generate MAC (C5 – C9) that punch holes in microbe membranes  In acute inflammation       Vasodilation vascular permeability mast cell degranulation (C3a, C5a) Leukocyte chemotaxin increases integrin avidity (C5a) As an opsonin, increases phagocytosis (C3b, C3bi) Clotting cascade  Cascade of plasma proteases  Hageman factor (factor XII)  Collagen, basement membrane, activated platelets converts XII to XIIa (active form)  Ultimately converts soluble fibrinogen to insoluble fibrin clot  activation of FXII activates: 1-kinin system 2-clotting system 3-the thrombin 4- complement system Kinin system  Leads to formation of bradykinin from cleavage of precursor (HMWK) Highmolecular-weight kininogen  Vascular permeability  Arteriolar dilation  Non-vascular smooth muscle contraction (e.g., bronchial smooth muscle)  Causes pain  Rapidly inactivated (kininases) Role of Mediators in Different Reactions of Inflammation