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 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 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