Chemical Mediators of Inflammation 2024 PDF

CHEMICAL MEDIATORS OF INFLAMMATION Definition: Any messenger that acts on blood vessels, inflammatory cells, or other cells to contribute to an inflammatory response. (Pretty much anything...) Exogenous – Endotoxins Endogenous – Plasma – Leukocytes – Endothelial cells – F...

CHEMICAL MEDIATORS OF INFLAMMATION Definition: Any messenger that acts on blood vessels, inflammatory cells, or other cells to contribute to an inflammatory response. (Pretty much anything...) Exogenous – Endotoxins Endogenous – Plasma – Leukocytes – Endothelial cells – Fibroblasts CHEMICAL MEDIATORS OF INFLAMMATION  CHEMICAL MEDIATORS OF INFLAMMATION Facts Mechanism of action – Receptor-ligand interactions (1o) – Direct enzymatic activity – Mediate oxidative damage  Extensive network of interacting chemicals High degree of redundancy Guarantees amplification and maintenance of inflammatory response Short t ½ and are harmful  CHEMICAL MEDIATORS Vasodilation – Prostaglandins, Nitric Oxide Increased Vascular Permeability – Vasoactive amines (histamine,serotonin), – C3a and C5a, – Bradykinin – Leukotrienes, – PAF,  CHEMICAL MEDIATORS OF INFLAMMATION The Basics Fever – IL-1, IL-6, TNF, Prostaglandins Pain – Prostaglandins, Bradykinin Tissue Damage – Neutrophil and Macrophage products –Lysosomal enzymes –Oxygen metabolites –NO  VASOACTIVE AMINES Increase Vascular Permeability Histamine and Serotonin – Mediators in the immediate active phase of increased permeability –Promotes contraction of smooth muscle –Stimulate cells to produce exotoxins – Serotonin found in rodent mast cells  Vasoactive Amines Continued Releasing Stimulators – Direct physical or chemical injury – Binding of IgE- Ag- complexes – Fragments of C3a and C5a – Histamine releasing factors (pmn’s and θ) – Cytokines (IL-1, IL-8) – Neuropeptides  PLASMA PROTEASES 3 interrelated systems are active within this category 1. Kinin system –Highly vasoactive 2. Complement system Vasoactive Chemotactic 3.Clotting system Vasoactive Cleaves C3  COMPLEMENT SYSTEM Plasma proteins - act against microbial agents Products of activated complement – Vascular permeability – Chemotaxis – Opsonization – Lysis COMPLEMENT SYSTEM Few reminders Classical pathway Alternate pathway Common pathway mportant inflammatory mediators – C3a and C5a (anaphylatoxins) –Cause release of histamine from mast cells –Lysosomal enzyme release in inflammatory cells – C5a –Activates lipoxygenase pathway –Chemotactic many inflammatory cells –Increases adhesion of leukocytes  COMPLEMENT SYSTEM And Inflammation C5b-9 membrane attack complex – Lyses cells – Stimulates arachidonic acid metabolism – Produces reactive oxygen metabolites  KININ SYSTEM BRADYKININ Activated by Hageman factor (XIIa) Bradykinin – Release of vasoactive nonapeptide bradykinin – Generated from the plasma Potent vasodilator  Increased vascular permeability Contraction of smooth muscle Produce pain Stimulates release of histamine Activates the arachidonic acid cascade  COAGULATION SYSTEM Clotting system Plasma proteins – Can be activated by Hageman factor Thrombin converts fibrinogen to fibrin – Fibrinopeptides are formed –↑vascular permeability –Chemotactic for leucocytes  Plasmin is important in lysing fibrin clots, – Activates Hageman factor (XII) ⇨ bradykinin – Cleaves C3 ⇨ C3a – "fibrin-split products" formed from fibrin breakdown –↑ vascular permeability  COAGULATION SYSTEM Clotting system Plasma proteins – Can be activated by Hageman factor Thrombin converts fibrinogen to fibrin – Fibrinopeptides are formed –↑vascular permeability –Chemotactic for leucocytes  HAGEMAN FACTOR Dependent Factors Factor XII of intrinsic coagulation cascade Activated by – Negatively charged surfaces – Platelets – Proteases from inflammatory cells  Causes – Coagulation – Activation of fibrinolytic system – Produces bradykinin – Activates complement – Provides an amplification system  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.  ARACHIDONIC ACID METABOLITES Roles in many biologic and pathologic processes – Inflammation 20-carbon polyunsaturated fatty acid – Derived directly from dietary sources – or by conversion of essential fatty acid linoleic acid  Via activation of cellular phospholipases – By mechanical, – chemical and – physical stimuli – or by other mediators 2 major pathways – Cyclooxygenase pathway – Lipoxygenase pathway.  CYCLOOXYGENASE PATHWAY 2 cyclooxygenase enzymes – COX-1 – COX-2  3 important products – Thromboxane A2 –Aggregates platelets and cause vasoconstriction – Prostacyclin (PGI2)  3 important products – Thromboxane A2 – Aggregates platelets and causes vasoconstriction – Prostacyclin (PGI2) – Endothelial cells inhibits platelet aggregation and causes vasodilation – Prostaglandins PGE2, PGF2 and PGD2 – Variety of actions on vascular tone and permeability  LIPOXYGENASE PATHWAY Leukotrienes Leukotrienes Leukotriene B4 is a potent chemotactic agent Leukotrienes C4, D4, E4 – Potent vasoconstrictors – Potent mediators of increased vascular permeability on venules only – Up to 1000 times as potent as histamine in producing increased vascular permeability  NOTE: – Some anti-inflammatory properties interfere with arachidonic acid metabolism –Corticosteroids interfere with phospholipase –Aspirin interferes with cyclooxygenase  PLATELET ACTIVATING FACTOR Aggregate platelets and cause release Bronchoconstriction and Vasoconstriction Vasodilation and ↑ vascular permeability ↑ leukocyte adhesion Leukocyte chemotaxis  CYTOKINES Transmitters for cell-to-cell chatting – Modulate cell function Primarily from activated macrophages and lymphocytes IL-1, IL-8, TNF  IL-I and TNF “Master Cytokines” Origin – Monocytes – Macrophages Similar in action Endothelium Acute phase proteins Fibroblasts  Other Cytokines Chemokines??? IL-5 – Eosinophils IL-6 – B and T cells IL-8 – Neutrophils – Lesser degree monocytes and eosinophils  GROWTH FACTORS Platelet derived growth factor Transforming growth factor β – Chemokines - Leukocytes and Mesenchymal Cells Important in regeneration and repair  NITRIC OXIDE (NO) Just say NO! Nitric oxide is synthesized from L-arginine 2 enzymes and many factors produce NO 3 effects – ♥♥ physical mediator of vascular tone – Host defense (forms perroxynitrite) – Signaling molecule – especially brain – Reduces platelet aggregation and adhesion – Inhibits several features of mast cell induced inflammation  3 effects – ♥♥ physical mediator of vascular tone – Host defense (forms perroxynitrite) – Signaling molecule – especially brain – Reduces platelet aggregation and adhesion – Inhibits several features of mast cell induced inflammation  Uncontrolled NO production – Can lead to massive peripheral – Vasodilation -Shock  LYSOSOMAL CONSTITUENTS Neutrophils, Monocyte/Macrophages – Enzymes and proteins within granules Cationic proteins – ↑ vascular permeability – Chemotactic Neutral proteases – Degrade ECM  OXYGEN-DERIVED FREE RADICALS Cause endothelial damage Protein destruction by inhibiting antiproteases Injury to variety of cells  Don’t forget the antioxidants – Ceruloplasmin – Transferrin – Superoxide dismutase – Catalase – Glutathione peroxidase