Inflammation (2 of 5) Ali Al Khader, M.D. Faculty of Medicine Al-Balqa’ Applied University Email: ali.alkhader@bau.edu.jo

We will discuss today: Cellular events: -Leukocyte recruitment -Leukocyte activation Some defects in leukocyte functions Termination of the acute inflammatory response

Leukocyte recruitment *Rolling + adhesion + transmigration…by adhesion molecules on WBCs & endothelial cells *Chemical mediators (chemoattractant/chemotactic cytokines/chemokines) affect the expression and affinity of adhesion molecules By selectin family of adhesion molecules…see next slide Bind to sialylated oligosaccharides = firm adhesion = transmigration = accumulation of WBCs near the wall 1- Margination 2- 3- 4- 5- = diapedesis In venules in systemic circulation and in capillaries in pulmonary circulation Leukocyte recruitment = platelet endothelial cell adhesion molecule By integrin on WBCs & their ligands on endothelial cells 6- Migration in the interstitium Collagenases secreted by WBCs degrade vascular basement membrane

Adhesion molecules Its ligand is activated due to IL-1 & TNF Expressed on the surface due to histamine and thrombin Its ligand is activated due to IL-1 & TNF On platelets and endothelial cells On endothelial cells On most leukocytes Expressed due to IL-1 & TNF They are glycoproteins

Tissue chemotactic factors for WBCs Bacterial products, particularly peptides with N-formylmethionine termini Cytokines, especially those of the chemokine family Components of the complement system, particularly C5 Products of the lipoxygenase pathway of arachidonic acid (AA) metabolism, particularly leukotriene B4 (LTB4)

Chemotactic molecule receptor on WBC change in WBC cytoskeleton Then by pseudopods: WBCs anchor to the ECM *In most forms of acute inflammation, neutrophils predominate in the inflammatory infiltrate during the first 6 to 24 hours and are replaced by monocytes in 24 to 48 hours Pseudomonal infection is an exception… Mention other 2 exceptions

Inflammation in myocardium after ischemic necrosis

Leukocyte activation Phagocytosis of particles Intracellular destruction of phagocytosed microbes and dead cells by -reactive oxygen and nitrogen species -lysosomal enzymes Liberation of molecules that destroy extracellular targets Secretion of inflammatory mediators -arachidonic acid metabolites -cytokines -others

Phagocytosis Either for the target or for an opsonin that coat the target = opsonization

Opsonins IgG immunoglobulins (antibodies) Breakdown products of the complement protein C3 (described later) Plasma carbohydrate-binding lectins called collectins bind to microbial surface antigens bind to microbial cell wall sugar groups

Phagocyte receptors for opsonins Fc receptor for IgG (= FcγRI) Complement receptors 1 and 3 (CR1 and CR3) for complement fragments C1q for the collectins

The main microbicidal molecules that the phagocyte uses for killing phagocytosed targets: ROS Enzymes…acid hydrolases elastase is the most important

Phagocyte ROS …after phagocytosis: -Induction of respiratory burst (oxidative burst): -rapid in oxygen consumption -glycogen catabolism (glycogenolysis) - glucose oxidation -production of ROS

Production of ROS in phagocytes NADPH oxidase (= phagocyte oxidase) is activated These events are in the phagolysosome Peroxinitrite (due to: NO + O2-)…NO is formed from arginine by the enzyme: inducible nitric oxide synthase (iNOS) = myeloperoxidase (in azurophilic granules of neutrophils) Halide (Cl-) powerful O2- dismutation = O2- H2O2

Other microbicidal molecules in the phagocyte granules Permeability-increasing protein (causing phospholipase activation and membrane phospholipid degradation) Lysozyme (causing degradation of bacterial coat oligosaccharides) Major basic protein…in eosinophils (special action against parasites) Defensins (peptides that kill microbes by creating holes in their membranes)

The WBCs also secrete their weapons against extracellular targets …examples: Phagocytic vacuole may remain transiently open to the outside before complete closure of the phagolysosome (regurgitation during feeding) Secretion of lysosomal enzymes when the phagocyte cannot engulf the target (frustrated phagocytosis)…example: secretion of enzymes against Ag-Ab complexes in some glomerular diseases (they are deposited on the immovable glomerular basement membrane so cannot be phagocytosed)

More about WBC defenses, Neutrophil Extracellular Traps (NETs) The neutrophil dies by this mechanism Mainly against bacteria and fungi

NETs

Defects in leukocyte functions

Termination of the acute inflammatory response Removal of chemical mediators…by different methods Normalization of vascular permeability Cessation of leukocyte emigration Apoptosis of extravasated neutrophils Inhibitory mediators released by leukocytes Phagocytosis and lymphatic drainage of dead soldiers, victims and edema fluid Some cytokines induce new vessel formation that brings nutrients and factors important for proliferation to repair the defect in tissue

Thank You