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Acute Inflammation. Dr Shoaib Raza. Acute Inflammation. Response of blood vessels, leading to accumulation of fluid & WBC in extravascular tissue Early, rapid, transient response characterized by: Vascular response Cellular response Followed by the process of repair . Vascular Changes .
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Acute Inflammation Dr Shoaib Raza
Acute Inflammation • Response of blood vessels, leading to accumulation of fluid & WBC in extravascular tissue • Early, rapid, transient response characterized by: • Vascular response • Cellular response • Followed by the process of repair
Vascular Changes • Changes in vascular flow & caliber • Vasodilation • ↑ vascular permeability and subsequent leakage of protein rich fluid in the interstitial spaces • ↑ viscosity of blood and sluggish flow (Stasis) • Lamellar flow is altered and now the cells especially PMN lie in close approximation to the endothelial cells
Increased vascular permeability • Hallmark of acute inflammation • Protein rich fluid (exudate) in the extravascular spaces • Formation of endothelial gap in venules • Direct injury to endothelium • Leucocyte dependent injury • Increases transcytosis • Angiogenesis
Summary of vascular changes • Fluid loss from vessel with increased permeability occurs in different phases • Immediate transient response (histamine, leukotrienes) • Delayed response (Kinins, complement system) • Prolonged response (endothelial injury e.g. in burns)
Cellular events during Acute Inflammation • Delivery of leukocytes towards site of injury, and their activation is a prime function of inflammation • Neutrophils and macrophages • Phagocytic cells • They ingest & kill bacteria & other microbes, eliminate necrotic tissue, and foreign body • Also produce growth factors
Reaction of Leukocytes in inflammation • The process involving leukocytes in inflammation consists of: • Recruitment from blood to extravascular tissue • Recognition of microbes, foreign body, necrotic tissue etc • Removal of the offending agent
Journey of leukocytes • In the lumen: • Margination, rolling, and adhesions • Endothelium also becomes more reactive to PMN • Migration across the endothelium and vessel wall • Migration in the tissue towards a chemotactic stimulus
Leukocyte adhesion to endothelium • Initial rolling mediated by family of selectins • P- selectins • L- selectins • E- selectins • Cytokines • TNF, IL-1, and other chemokines • Induce coordinate expression of adhesion molecules • 1-2 hours, endothelial cells express E-selectins
Adhesion Molecules • Histamine, thrombin, PAF, etc, stimulate redistribution of P-selectins • Leukocytes express L- selectins and ligand for P & E- selectins • Bind to the complementary molecule on endothelial surface • Low affinity reactions with a fast off-rates • Leukocyte bind, detach, and bind again, thus roll along the endothelial surface • Firm adherence is mediated by integrins, present on the leukocyte surface
Endothelial/leukocytes Adhesion Molecules • P-Selectins / sialyl-Lewis X modified protein • Rolling of PMN, monocytes, lymphocytes • E-Selectins / sialyl-Lewis X modified protein • Rolling, adhesion (PMN, T-cells, Mac) • GlyCam-1, CD134/ L-selectins • Rolling (PMN, Mono) • ICAM-1 (Immunoglobulin family)/CD11, CD18 (β2), integrins (LFA, MAC-1) • Adhesion, transmigration (lymphocyte, eosinophil, monocyte) • VCam-1 (Immunoglubulin family) / VLA-4 (β2), Integrin • Lymphocyte homing to high endothelial venules
Leukocyte Migration Through Endothelium • Migration through endothelium • Transmigration • Diapedesis • Occurs mainly in postcapillary venules • Through interendothelial spaces • PECAM-1, CD31 • Collegenase help in disrupting the basement membrane
Chemotaxis of Leukocytes • Chemotaxis • Locomotion oriented along a chemical gradient • Chemoattractants • Exogenous • Bacterial products, lipids, etc • Endogenous • Cytokines (IL-8) • Complement components (C3a, C5a) • Arachidonic acid metabolites (LTB4)
Nature of Leukocyte Infiltrate • Varies with the age of inflammatory response, and type of stimulus • 6-24 hours, neutrophils • 24-48 hours, monocytes • Exemptions • Pseudomonas induce continuous recruitment of PMN • Lymphocytes in viral infections • Eosinophil in hypersensitivity reactions
Recognition of Microbes & Dead Tissues • Phagocytes need to be activated after chemotaxis • Response of leukocytes consists of two sequential events • Recognition of the offending agent • Activation of leukocytes for ingestion and destruction of the offending agent • Receptors on leukocytes are • Toll like receptors (TLRs) • 10 mammalian TLRs have been identified • Recognize bacterial LPS, proteoglycans, etc • G Protein-coupled receptors • Recognize short bacterial peptides • Receptors for opsonins • Opsonins are protein that coat microbes • C3b, IgG, lectins • Receptors for cytokines • IFN-γ
Removal of the offending agent • Leukocytes activation • Receptors binding induces several responses • ↑ in cytosolic calcium • Enzyme activation (phospholipase A2) • Results in • Phagocytosis • Recognition • Engulfment • Killing and degradation
Phagocytosis • Involves three sequential steps • Recognition and attachment • Engulfment • Killing or degradation • Receptors for recognition • Mannose receptors (lectins) • Scavenge receptors • Opsonization greatly enhances phagocytosis
Engulfment • After receptor binding, pseudopodia flow around it, and plasma membrane pinches off to form a vesicle (phagosome) • Phagosome fuses with lysosome forming phagolysosome • Some granules may also release in extracellular spaces
Killing & Degradation • Elimination of infectious agent and necrotic material • Within neutrophil and macrophages • Reactive oxygen species are formed within activated neutrophils • Rapid oxidative reaction is triggered by activating signals, is called as respiratory burst • Important enzymes are • Phagocyte oxidase • Myeloperoxidase • H2O2-MPO-Halidase system
Leukocytes Products • Macrophages produce growth factors • VEGF, FGF, • May cause injury to normal cells and tissue, under: • Collateral damage • Autoimmune disorders (inappropriately directed inflammatory response) • When the hosts react excessively against usually harmless environmental substances as in allergic/hypersensitive reactions
Fate of Acute Inflammation • Inflammatory mediators are short lived • Neutrophil have shorter half life • Stop signals • IL-10, TGF-β, cholinergic discharge, protectins, etc • Acute inflammatory response is terminated • Acute inflammation may be • Completely resolved • Pus and abscess formation • Gets prolonged into chronic inflammation