Chemical Mediators of INFLAMMATION

Classes of Chemical mediators Vasoactive Amines Kinin System Clotting System Complement system Arachidonic acid metabolites Platelet Activating factors Nitric oxide, Neuropeptides and Others Cytokines & Chemokines

Chemical Mediators of Inflammation: Properties They are preformed chemicals Bind to specific receptors and act Stimulate the release of other mediators Can act on one or few target cell types Once activated these are short lived

Vasoactive amines-Histamine Present as Preformed stores in cells First among the chemical mediator to be released Present in Mast cells, basophils & Platelets Causes Arteriolar dilatation, increases permeability. Acts on H1 receptors on endothelial cells

Mast cell Basophil B Lymphocyte Plasma cell LGL Monocyte NK cell/ Virocytes Macrophage/ Histiocyte Liver- Kuffer cell Brain- Microglial cell Spleen- Sinusoidal Macroph Skin- Dendritic cell Bone- Osteoclasts Joint- Sinoviocytes Lung- Dust cells Monocyte

Membrane Phospholipids Breakdown Antigen Ig E Ab Ig E receptor Membrane Phospholipids Breakdown Degranulation Histamine Protease ECF NCF Leucotrienes : B4,C4,D4 Prostaglandins

Vasoactive Amines-Serotonin 5-Hydroxytryptamine Action similar to Histamine Platelets, Mast cells, Enterochromaffin cells. Causes platelet aggregation, increased permeability. Acts along with PAF.

Allergies Histamine causes blood vessels to widen and become leaky. Fluid and white blood cells leave capillaries. The area of leakage becomes hot, red and inflamed

Pain when injected to skin Bradykinin functions Increases vascular Permeability Blood vessel dilatation Contraction of Smooth muscle Pain when injected to skin

Classic pathway - activation by immunoglobulin bound to microbial agents

Alternate pathway - activation by microbial surface proteins

Biological Functions of Complements. C3a, C5a Mast cell and platelet Anaphylaxis Degranulation C5a Activates Lipoxygenase Pathway C3b Potentiating of Ab response, Opsonisation of cells and lysis. C5b-9 (MAC) Cell lysis.

Complement System C3a and C5a: Anaphylotoxins C3b and IgG: Opsonizing agents C5b-9: MAC—Membrane attack complex

Disorders of Complement System: Deficiency of MAC: Increased Neisseria infection. Deficiency of C1 Inhibitor: Her. Angioneuritic edema Def. of DAF and CD 59 (MIRL): PNH Def. of C2 & C4: Increased SLE association. Def. of C3: Increased infections.

Cell membrane Phospholipids X Phospholipases Steroids Arachidonic acid X NSAIDs 5 Lipooxygenase Cyclooxygenase 12Lipooxygenase Leukotriens b4 Prostaglandins g 2, h2 Chemotaxis Prostacyclin, pg I 2 Thromboxane a2 Leukotriens c4d4e4 Vasoconstriction Vasodilation Bronchospasm Vasoconstriction Lipoxins a4, b4 Pg d2, e2, f2 alpha Vasodilation Inhibit Chemotaxis Vasodilation

Bronchial Asthma Leukotrienes, Histamine Effects

Inflammatory Actions of Arachidonic acid metabolites Vasoconstriction TXA2, LTC4, D4, E4 Vasodilatation PGI2, PGE2, PGD2 Increased vascular Permeability LTC4, D4, E4 Chemotaxis LTB4 WBC adhesion Lipoxins A4, B4.

Acute Phase Reactions Fever Increased sleep Decreased Appetite Shock Neutrophilia

Cytokines: Lymphokines Monokines Interleukins Chemokines Autocrine action Paracrine action Endocrine effect

of division and IFN gamma release (and other mediators) Interleukin-2 (IL-2) IL-2 secretion T cell NK Increase in NK Cell activity B cell Stimulation of division of division and IFN gamma release (and other mediators) Monocyte Activation

Remodeling Collagenases Macrophage- T lymphocyte Interaction Activated T-Lymphocyte IFN ﻻ Activated MACROPHAGES TISSUE INJURY Proteases Reactive O2 species AA metabolites Nitric oxide NCF FIBROSIS GF: PDGF, FGF, TGF β Fibrogenic cytokines Angiogenesis Remodeling Collagenases

Macrophage & Lymphocyte interaction IL-12 Activated T-Lymphocyte Activated MACROPHAGES IFN γ TNF TNF IL-1

NITRIC OXIDE Called EDRF (Endothelium derived relaxing factor). Soluble gas produced by endothelium, macrophages & neurons Induces cyclic GMP which mediated relaxation of smooth muscle cells. Half life is only in seconds. NO is synthesized from L-arginine by enzyme NO synthase.

NITRIC OXIDE: …., Potent vasodilator Reduces platelet aggregation Inhibits mast cell induced inflammation Abnormalities in endothelial NO production leads to Atherosclerosis, Diabetes, Hypertension. NO is also Microbicidal: Reactive nitrogen intermediates acts like free radicals, which are antimicrobial.

Acute Inflammation Components Physiology Symptoms Release of soluble mediators Vasodilation Increased blood flow Extravasation of fluid (permeability) Cellular influx (chemotaxis) Elevated cellular metabolism heat (calore) redness (rubor) swelling (tumor) pain (dolore)

Acute Inflammation Components Physiology Symptoms Release of soluble mediators Vasodilation Increased blood flow Extravasation of fluid (permeability) Cellular influx (chemotaxis) Elevated cellular metabolism heat (calore) redness (rubor) swelling (tumor) pain (dolore)

Acute Inflammation Components Physiology Symptoms Release of soluble mediators Vasodilation Increased blood flow Extravasation of fluid (permeability) Cellular influx (chemotaxis) Elevated cellular metabolism heat (calore) redness (rubor) swelling (tumor) pain (dolore)

Acute Inflammation Components Physiology Symptoms Release of soluble mediators Vasodilation Increased blood flow Extravasation of fluid (permeability) Cellular influx (chemotaxis) Elevated cellular metabolism heat (calore) redness (tubor) swelling (tumor) pain (dolore)

Acute Inflammation Components Physiology Symptoms Release of soluble mediators Vasodilation Increased blood flow Extravasation of fluid (permeability) Cellular influx (chemotaxis) Elevated cellular metabolism heat (calore) redness (tubor) swelling (tumor) pain (dolore)

Summery: Histamine Mast cell Vasodilatation Serotonin Platelets Prostaglandins Leukocytes Fever, Vasodil. Leukotrienes Chemotaxis PAF Degranulation Nitric oxide Endothelium Killing microbes Cytokine IL-1, TNF Macrophages Fever, Anorexia Chemokines Complements Liver Activation Kinins Pain, SM contra

SWELLING REDNESS PAIN HEAT LOSS OF FUNCTION Chemical Mediators of INFLAMMATION: Summery Stimuli for INFLAMMATION Physical Chemical Pathogen Antigen Immunological Mast cell Basophil Platelets Lymphocytes Macrophages Neutrophils Macrophages Eosinophils Plasma, Liver Histamine Prostaglandins Kinins Complements Plasmin CYTOKINES Vasodilatation Increased Vasc. Permeability Vasodilatation Increased Vasc. Permeability Smooth m contract Pain Chemotaxis WBC Adhesion MAC-Phagocytosis Fibrin Break down Acute Phase Rn WBC Adhesion Chemotaxis Chemo attraction SWELLING REDNESS PAIN HEAT LOSS OF FUNCTION

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