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 (β 2 ), integrins (LFA, MAC-1)  Adhesion, transmigration (lymphocyte, eosinophil, monocyte)  VCam-1 (Immunoglubulin family) / VLA-4 (β 2 ), 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 (LTB 4 )

Nature of Leukocyte Infiltrate  Varies with the age of inflammatory response, and type of stimulus  6-24 hours, neutrophils  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 A 2 )  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  H 2 O 2 -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