Acute InflammationDr 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