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 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 Increased Vascular Permeability Prostaglandins, Nitric Oxide Increased Vascular Permeability Vasoactive amines (histamine, serotonin), C3a and C5a, Bradykinin, Leukotrienes, PAF, Chemotaxic Leukocyte Activation C5a, LTB4, Chemokines

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 and Vascular Permeability Histamine and Serotonin Mediators in the immediate active phase of increased permeability Promotes contraction of smooth muscle Stimulates to cells to produce eotaxins Serotonin found in rodent mast cells

Vasoactive Amines Releasing Stimulators 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 Kinin system Complement system Clotting system 3 interrelated systems are active within this category Kinin system Highly vasoactive Complement system Vasoactive Chemotactic Clotting system Cleaves C3

COMPLEMENT SYSTEM Plasma proteins - act against microbial agents Products of activated complement Vascular permeability Chemotaxis Opsonization Lysis

COMPLEMENT SYSTEM Classical pathway Alternate pathway Common pathway Few reminders Classical pathway Alternate pathway Common pathway Important 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 C5b-9 membrane attack complex Lyses cells And Inflammation C5b-9 membrane attack complex Lyses cells Stimulates arachidonic acid metabolism Produces reactive oxygen metabolites

KININ SYSTEM 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

COMPLEMENT SYSTEM Classical pathway Alternate pathway Common pathway Few reminders Classical pathway Alternate pathway Common pathway Important 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 C5b-9 membrane attack complex Lyses cells And Inflammation C5b-9 membrane attack complex Lyses cells Stimulates arachidonic acid metabolism Produces reactive oxygen metabolites

COAGULATION SYSTEM Plasma proteins 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 Plasma proteins 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

HAGEMAN FACTOR Factor XII of intrinsic coagulation cascade 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 Esterified in membrane phospholipids Must first be released from phospholipids 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 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 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 Origin Similar in action Endothelium Acute phase proteins “Master Cytokines” Origin Monocytes Macrophages Similar in action Endothelium Acute phase proteins Fibroblasts

Other Cytokines IL-5 IL-6 IL-8 Eosinophils B and T cells Neutrophils 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) Nitric oxide is synthesized from L-arginine 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 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