Inflammation Lecture II

Defect in leukocytes function Defect in adhesion Leukocyte adhesion defect-1 due to defect in integrin. Leukocyte adhesion defect-2 due to defect in sialyl- Lewis X. Defect in chemotaxis or phagocytosis Chediak-Higashi syndrome. Defect in microbicidal activity Chronic granulomatous disease

Chemical Mediators A substances which play a role in genesis and modulation of inflammatory reaction. They are responsible for: 1.Vasodilatation. 2.Increased permeability of the blood vessels. 3.Emigration of WBC (Chemotactic agent).

Mediators of acute inflammation Plasma factors synthesized mainly in liver Kinin system Factor XII = coagulation system (Hageman factor) activation Coagulation system Plasma proteins C3a C5a C3b C5b-C9 anaphylatoxins Complement activation opsonin MAC

Chemical Mediators of Inflammation A/ Vasoactive Amines 1) Histamine: secreted from mast cells, basophils & platelets. 2) Serotonin: secreted from platelets, enterochromaffin cells. Effects: arteriolar vasodilatation & increase vascular permeability.

B/ Arachidonic Acid (AA) Metabolites AA present in the cell membrane phospholipids. Release from phospholipids through the action of phospholipase enzyme by mechanical, chemical & physical stimuli. AA metabolism proceeds along 1 of 2 pathways Cyclo-oxygenase pathway------Prostoglandins. Lipo-oxygenase pathway------------Leukotriens.

Arachidonic Acid Metabolites Cyclo-oxygenase pathway -Thromboxane A2 Vasoconstriction Platelet aggregation -Prostacyclin (PGI2) Vasodilatation Inhibits Platelet aggregation -PGD2, PGE2 & PGF2 VD & edema -PGE2: Fever Pain Lipo-oxygenase pathway -HETE: Chemotaxis -LTB4: Aggregation of neutrophils -LTC4, LTD4, LTE4 Vasoconstriction Bronchospasm Increase vascular permeability

C/ Platelet-Activating Factor Synthesized from membrane phospholipids through the action of phospholipase A2 in basophils, endothelial cells & neutrophils. Effects of platelate –Activating factor Platelet aggregation. V.D. & increase vascular permeability. Chemotaxis. Smooth muscle contraction.

Polypeptides produced by activated lymphocytes & macrophages. D) Cytokines Polypeptides produced by activated lymphocytes & macrophages. It involved in cellular immunity & inflammatory responses. IL-1 & TNF Acute phase reaction including fever & Neutrophilia. Promote endothelial secretion of PG & NO. Induce fibroblastic proliferation & collagen synthesis. IT-6 Acute phase reactions. IT-8 Chemotactant & neutrophil activating agent.

E) Nitric Oxide (NO) Soluble free radical gas synthesized by endothelial cells, macrophages & specific neurons in the brain. Effect Vascular smooth muscle relaxation causing vasodilatation. Decreased platelet aggregation & adhesion. Microbicidal agent.

F) Lysosomal Constituents Potentially act as inflammatory mediators when released from neutrophils & macrophages. Effect: Destruction of ECM. Direct cleavage of C3 & C5.

G) Oxygen Free Radicals Superoxide (O2-), OH-, H2O2 & NO Effects Endothelial cell damage causing increase vascular permeability. Activation of proteinases. Injury to surrounding cells.

Present as inactive form in the plasma H/ Plasma Proteases 1)Complement System Present as inactive form in the plasma Vascular effect (anaphylotaxins): C3a, C5a & C4a causing V.D. & increase vascular permeability. Leukocyte adhesion, chemotaxis & activation: C5a Phagocytosis: C3b & C3b1 act as opsonin.

Activated by activation of Hageman factor (XII) 2) Kinin System Activated by activation of Hageman factor (XII) Bradykinin: increase vascular permeability , V.D., pain & smooth muscle contraction. Kallikrein: has chemotactic activity.

3) Clotting System A cascade activated by Hageman factor (XII) resulting in conversion of fibrinogen to fibrin. Fibrinopeptides: increase vascular permeability & chemotaxis.

4) Fibrinolytic System: Plasmin: lyses fibrin clots, degrades fibrin to fibrin degradation products. Fibrin degradation products: Increase vascular permeability.

Microscopic appearance of acute inflammation Congestion of blood vessels. Exudation of fluid. Exudation of inflammatory cells mainly neutrophils.

Types of acute inflammation 1. Catarrhal Acute inflammation + mucus hyper secretion of mucus membrane (common cold). 2. Serous Low protein content, low cellular fluid (pleural effusion). 3. Suppurative (Purulent) Pus: creamy yellow or blood stained fluid consist of N, M.O, & tissue debris (acute appendicitis). Abscess: Focal localized collection of pus material. Empyema: Collection of pus in the hallow organ. 4. Fibrinous Accumulation of thick exudate rich in fibrin, which may resolve by fibrinolysis or organize into thick fibrous tissue. Fibrinous inflammation –bread &butter appearance to the inflamed serous membrane.

Morphologic patterns of acute inflammation Serous inflammation: Tissue fluid accumulation indicating a modest increase in vascular permeability Pleura , pericardium, peritoneum: effusion Blister in burns

Fibrinous inflammation: More marked increase in vascular permeability, with exudates containing large amounts of fibrinogen Involvement of serosal surfaces ( pericardium or pleura) : fibrinous pericarditis or pleuritis

Suppurative or purulent inflammation: Production of purulent exudates consisting of leukocytes and necrotic cells. An abcess refers to a localized collection of purulent inflammatory tissue accompanied by liquefactive necrosis.