Inflammation Dr. Ahmad Hameed MBBS,DCP, M.Phil

Chemical Mediators and regulators of inflammation Chemical mediators that are responsible for vascular and cellular events of inflammation. Mediators may be produced locally by cells at inflammation, or may be derived from circulating precursors (typically synthesized by the liver) that are released at the site of inflammation. Cell-derived mediators are  Sequestered intracellular granules or synthesized de novo Plasma derived mediators are inactive which undergo proteolytic cleavage to acquire biologic activity..

Chemical Mediators and regulators of inflammation Most mediators act by binding to specific receptors on different target cells. Diverse action Direct action The actions of most mediators are tightly regulated and short lived Quickly decay Inactivated by enzymes Eliminated inhibited

Cell DerivedMediatorsSourceActions Preformed mediators in secretory granules HistamineMast cells, basophils, platelets Vasolidation, increased vascular permeability, endothelial activation SerotoninPlateletsVasoconstriction Newly synthesizedProstaglandinsAll leukocytes, mast cellsVasodilation, pain, fever LeukotrienesAll leukocytes, mast cellsIncrease vascular permeability, chemotaxis, leukocyte adhesion and activation Platelet- activitating factor All leukocytes, ECVasodilation, increase vascular permeability, leukocyte adhesion, chemotaxis, degranulation, oxidative burst. Reactive oxygen species All leukocytesKilling microbes, tissue damage Nitric oxideMacrophages, ECVascular smooth muscle relaxation; killing of microbes CytokinesMacrophages,lymphocytes, EC, mast cells Local; endothelial activation (expression of adhesion molecules) systemic: fever, metabolic abnormalities, hypotension (shock) NeuropeptidesLeukocytes, nerve fibers

Plasma protein- derived MediatorsSourceActions Compliment activationC3a (anaphylatoxins ) Plasma (Liver) Leukocyte chemotaxis and activation, direct target killing (MAC), yasodilation (mast,cell stimulation) C5a (anaphylatoxins ) Plasma (Liver) C3bPlasma (Liver) C5b-9 (membrance attack complex) Plasma (Liver) Factor XII (hageman factor) activation Kinin system (bradykinin) Plasma (Liver) Increased vascular permeability, smooth muscle contraction, vasodilation, pain Coagulation / fibrinolysis sytem Plasma (Liver)

Cell-Derived Mediators Tissue macrophages, mast cells, and endothelial cells, leukocytes Vasoactive Amines HISTAMINE Richest source Mast cells ( C.T, B.V) Basophils Platelets Release in response to 1. Physical injury (trauma, cold, heat) 2. Immune reactions (Antibody to mast cells) 3. Anaphylatoxins (C3a & C5a)

1. Histamine Releasing protein (H.R.P) from leucocytes 2. Neuropeptides (Substance P ) 3. Cytokines ( IL-1, IL-8) Action Immediate transient response (main) Dilatation of arterioles Increase permeability of venules Contricts large arteries Acts on microcirculation / bind to H1 receptors on endothelial cells

SEROTONIN 5HT Similar action Present in platelets, entero chromaffin cells & neurons Neurotrasmitter and regulate intestinal motility When platelet aggregation occurs  release serotonin Mast cells  PAF  platelet aggregation

Archidonic Acid Metabolites: Prostaglandins, Leukotrienes and Lipoxins Microbial Products + Mediators of Inflammation ↓ Arachidonic Acid Prostaglandins Leukotrienes

AA Metabolites Cyclooxygenase pathway PGs are Produced by mast cells, macrophages, endothelium and others PGE 2,PGD 2,PGF 2α  Vasodilation  Potentiates Edema formation  Involved in pathogenesis of pain and fever PGI 2  Produced by prostacyclin synthase in endothelial cell  Vasodilation, Inhibits Platelet aggregation TXA 2  Produced by Thromboxane synthase in platelets  Vasoconstriction & stimulates platelets aggregation, unstable and converts to TXB 2

Production of arachidonic acid metabolites and their roles in inflammation.

Lipoxygenase Pathway LTs are secreted mainly by leukocytes and chemoattractants for leukocytes. LTA 4 LTB 4  Produced by neutrophils & some macrophages  Chemotactic agent for neutrophils LTC 4 LTD 4 & LTE 4  Produced by mast cells  Vasocontriction + bronchospasm + Intravascular Permeability

Anti-inflammatory Drugs that Block Prostagladin Production NSAID Inhibit cyclooxygenase Prevent biosynthesis of all PG Treat pain and fever Cyclooxygenase inhibitor Two isoforms - COX-1/COX-2 COX-1 Expressed on most tissues produced in response to inflammation stimulate prostaglandins COX-2 Absent most tissues Developed that they will not affect protective function of prostaglandins Increased risk of cerebrovascular and cardiovascular events

Lipoxygenase Pathway Lipoxins (Anti inflammatory mediators )  Endogenous antagonists of Leukotrienes ie inhibit neutrophil chemotaxis and adhesion to endothelium  Platelet adherent to neutrophils from LXA 4 and LXB 4

Cortisol Reduces vascular permeability and edema Decreases prostglandin production by preventing release of AA by inhibiting phospholipase A 2

Platelet-Activating Factor It is generated from a lipid complex stored in cell membranes; Produced by WBCs & endothelial cells induces platelet aggregation; Causes Vasoconstriction, Bronchoconstriction It activates neutrophils and is a potent eosinophil chemoattractant; It contributes to extravascularization of plasma proteins and so, to edema.