Acute Inflammation Dr Shoaib Raza. Acute Inflammation Response of blood vessels, leading to...
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Transcript of Acute Inflammation Dr Shoaib Raza. Acute Inflammation Response of blood vessels, leading to...
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Acute InflammationDr Shoaib Raza
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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
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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
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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
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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)
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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
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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
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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
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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
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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
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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
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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
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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)
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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
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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
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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
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Phagocytosis Involves three sequential steps
Recognition and attachment Engulfment Killing or degradation
Receptors for recognition Mannose receptors (lectins) Scavenge receptors Opsonization greatly enhances phagocytosis
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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
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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
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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
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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