2- Mediators of Inflammation.pdf

Mediators of Inflammation  Chemical mediators and regulators of inflammation Cell derived: Mediators may be produced locally by cells at the site of inflammation. Connective tissue, Endothelium, Necrotic cells Plasma derived: derived from circulating inactive precur...

Mediators of Inflammation  Chemical mediators and regulators of inflammation Cell derived: Mediators may be produced locally by cells at the site of inflammation. Connective tissue, Endothelium, Necrotic cells Plasma derived: derived from circulating inactive precursors in plasma (typically synthesized by liver) that are activated at site of inflammation stimuli –production of: Primary Mediators - Secondary Mediators amplify or counter-act the primary mediators  Chemical mediators of inflammation Actions: 1.bind to receptors 2. act as enzymes 3. oxidative damage 4. Tightly regulated and short lived. Action terminated - by decay or inactivation by enzymes 5.act differently on different target cells  Cell derived /local Pre-formed in granules: a. Histamine – mast, basophils, platelets b. Serotonin - platelets c. lysosomal enzymes – neutrophils, macrophages Newly synthesized a. Prostaglandins - all leukocytes, platelets, endothelium b. Leukotriene - all leukocytes c. Platelet-activating factor - all leukocytes, endothelium d. Reactive oxygen - all leukocytes e. Cytokines - macrophages, lymphocytes f. Nitric Oxide - macrophages  Cell-derived mediators Pre-formed: Histamin: Mast cells, basophils, platelets Vasodilation, increased vascular permeability, endothelial activation. Inactivated by histaminase Serotonin: Platelets. Vasodilation, increased vascular permeability Stimuli for release In platelets: contact with collagen, thrombin, ADP, PAF, ag-ab complexes In mast cells: Physical (Trauma, Heat, Cold), Immune reactions, Complement components (C3a, C5a), Cytokines (IL1, 8), Nuropeptides, factors from leukocytes  Cell-derived mediators Preformed- Lysosomal Enzymes Neutrophils have: specific granules containing: lysozyme, collagenases, lactoferrin, plasminogen activator. secrete extracellularly azurophil granules containing: MPO, acid hydrolases, neutral protease Termination: decay or enzymatic check/balance: anti-proteases  Cell-derived mediators Newly synthesized Arachidonic acid metabolites also called Eicosanoids: AA is a polyunsaturated fatty acid synthesized from dietary linoleic acid exists in esterified form in membrane PL released by Phospholipases through physical, chemical stimuli or mediators Sources: leukocytes, mast, platelets, endothelium  Cell-derived mediators Prostaglandins: vasodilatation ( edema, pain, fever) Thromboxanes: vasoconstriction, platelet aggregation Leukotrienes: vasoconstriction, increased permerbility, bronchospasm, chemotactic for neutrophils Lipoxins: negative regulator of leukocyte action  AA metabolism membrane phospholipids p.lipases x steroids AA NSAIDs LOX COX LT PG (A4 toE4 ) ( D2 toI2) increase permeability pain, fever bronchospasm  Platelet Activating Factor Acetyl glycerol phosphocholine derived from Phospholipid – phospholipase A2 Sources: neutrophils, monocytes, basophils, platelets, endothelial cells Actions: on cell via G protein coupled receptor platelet aggregation, degranulation leukocyte activation (Chemotaxis, adhesion, degranulation) Vasodilatation & increase permeability bronchoconstriction Stimulate synthesis of eicosanoids  Nitric oxide Free radical gas, synthesis enzyme NO synthetase, induced by inflammatory cytokines IL-1, TNF, IFNγ and endotoxins 3 types Source: neurons, macrophages, endothelium Actions: Endothelium: Paracrine - vasodilatation by smooth muscle relaxation macrophages - antimicrobial & killing tumor cell Inhibit neutrophil & platelet activation Neuron: Regulate neurotransmitter release in CNS  Cytokines Nature: proteins (Polypeptides) source: lymphocytes and macrophages Types: Coloney Stimulating Factor, Chemokines IL (IL- 1,) and TNF Actions: autocrine, paracrine, endocrine secrete in response to: endotoxins, AA comp. And physical injury actions: 1.acute phase reactions 2.on endothelium TNF controls 3.on white cells body mass 4.on fibroblasts  , in acute inflammation TNF, IL-1, IL-6 and chemokines Macrophages, lymphocytes, endothelial cells, mast cells Principal role in inflammation is endothelial activation. TNF & IL-1 stimulate expression of adhesion molecules on endothelial cells in chronic inflammation: IFNγ, IL-12, IL-17  Plasma protein – derived mediators 4 interrelated systems are active within this category 1.Kinin system 2.Complement system 3.Clotting system 4.Fibrinolytic system All linked by initial activation of Hageman factor (factor XII of intrinsic coagulation cascade. It’s a protein synthesized by liver. circulates in an inactive form until it encounters collagen, basement membrane or activated platelets.  KININ SYSTEM BRADYKININ Activated by Hageman factor (XIIa) Leads to formation of Bradykinin Potent vasodilator Increased vascular permeability Contraction of smooth muscle Produce pain Stimulates release of histamine Activates the arachidonic acid cascade  IMPORTANT NOTE Activated Hageman factor (factor XIIA) initiates the clotting, fibrinolytic and kinin systems. The products of this initiation (kallikrein, factor XIIA, and plasmin, but particularly, kallikrein) can, by feedback, activate Hageman factor, resulting in significant amplification of the effects of the initial stimulus.  COAGULATION SYSTEM Hageman factor results in activation of Factor Xa causes increased vascular permeability and leuckocyte emigration Thrombin activation causes fibrinogen to generate fibrin clot. Thrombin induces leuckocyte adhesion to endothelium, increases vascular permeability and chemotaxis  Fibrinolytic system Hageman factor activates fibrinolytic system alongwith clotting system. Plasminogen activator and kallikrein converts plasminogen into Plasmin Plasmin 1.causes formation of fibrin degradation products which in turn causes increased vascular permeability. 2.Cleaves C3 into C3a which results in vasodilation and increased vascular permeability.  COMPLEMENT SYSTEM The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism Plasma proteins – C1 – C20 act against microbial agents by generating porelike membrane attack complex (MAC) Functions of complement Opsonization - enhancing phagocytosis of antigens Chemotaxis - attracting macrophages and neutrophils Cell Lysis - rupturing membranes of foreign cells  COMPLEMENT SYSTEM Vascular effects C3a & C5a causes histamine release from mast cells which in turn causes vasodilation and increased vascular permeability. C5a activates lipoxygenase pathway of AA metabolism Leuckocyte activation, adhesion and chemotaxis C5a activates leuckocytes & increases affinity for integrins Phagocytosis C3b act as opsonin thus promoting phagocytosis  Cytokines Polypeptides, in acute inflammation TNF, IL-1, IL-6 and chemokines Macrophages, lymphocytes, endothelial cells, mast cells Principal role in inflammation is endothelial activation. TNF & IL-1 stimulate expression of adhesion molecules on endothelial cells in chronic inflammation: IFNγ, IL-12, IL-17  Chemokines Family of small proteins Two major groups: CXC & CC IL – 8 belongs to CXC group. Leukocytes, activated macrophages Chemotaxis, leukocyte activation  Lysosomal Enzymes of Leukocytes most important of lysosomal molecules Acid proteases generally active only within phagolysosomes Neutral proteases: elastase, collagenase, and cathepsin, are active in the ECM and cause destructive, deforming tissue injury by degrading elastin, collagen, basement membrane, and other matrix proteins ARACHIDONIC ACID METABOLITES  CYCLO-OXYGENASE PATHWAY Products of this pathway include prostaglandin E2 (PGE2), PGD2, PGF2α, PGI2 (prostacyclin), and thromboxane A2 (TXA2), platelets contain the enzyme thromboxane synthase, and hence TXA2, a potent platelet-aggregating agent and vasoconstrictor Endothelial cells, on the other hand contain prostacyclin synthase, which is responsible for the formation of PGI2, a vasodilator and a potent inhibitor of platelet aggregation  Contd… PGD2:major metabolite in mast cells; along with PGE2 and PGF2α, it causes vasodilation and potentiates edema formation. PGE2 augments pain sensitivity to a variety of other stimuli and interacts with cytokines to cause fever  LIPOXYGENASE PATHWAY 5-Lipoxygenase is the predominant AA- metabolizing enzyme in neutrophils 5-hydroperoxy derivative of AA, 5-HPETE (5- hydroperoxyeicosatetraenoic acid), is quite unstable and is either reduced to 5-HETE (5- hydroxyeicosatetraenoic acid) (which is chemotactic for neutrophils) or converted into a family of compounds collectively called leukotrienes  leukotrienes The first leukotriene generated from 5-HPETE is called leukotriene A4 (LTA4), which in turn gives rise to LTB4 or LTC4. LTB4 is produced by neutrophils and some macrophages and is a potent chemotactic agent for neutrophils LTC4 and its subsequent metabolites, LTD4 and LTE4, are produced mainly in mast cells and cause vasoconstriction, bronchospasm, and increased vascular permeability  lipoxins Lipoxins A4 & B4 inhibit neutrophil chemotaxis and adhesion to endothelium, thus serving as endogenous antagonists of leukotrienes. Platelets that are activated and adherent to leukocytes are also important sources of lipoxins.  Principal Inflammatory Actions of Arachidonic Acid Metabolites (Eicosanoids) Action Eicosanoid Vasodilation PGI2 (prostacyclin), PGE1, PGE2, PGD2 Vasoconstriction Thromboxane A2, leukotrienes C4, D4, E4 Increased vascular permeability Leukotrienes C4, D4, E4 Chemotaxis, leukocyte adhesion Leukotriene B4 Thank you