1. Inflammation (2 of 5) Ali Al Khader, M.D. Faculty of Medicine
Al-Balqa’ Applied University

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

3. 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

4. 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

5. 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)

6. 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

7. Inflammation in myocardium after ischemic necrosis

8. 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

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

10. 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

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

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

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

14. 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 = O H2O2

15. 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)

16. 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)

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

18. NETs

19. Defects in leukocyte functions

20. 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

21. Thank You