Acute inflammation 3

1. Acute inflammation 3 By Dr. S. Homathy

2. This is augmented by slowing of the blood flow and increased vascular permeability, • fluid leaves the vessel causing • leukocytes to settle-out of the central flow column • and “marginate” along the endothelial surface • Leucocytes accumulate at the periphery of vessels • Margination

3. Normal flow • stasis

4. Rolling • Endothelial cells and leukocytes have complementary surface adhesion molecules • which briefly stick and release causing the leukocyte to roll along the endothelium • like a tumbleweed until • it eventually comes to a stop as mutual adhesion reaches a peak

5. Rolling • Then WBC tumble on the endothelial surface • Transiently sticking along the way- rolling • Lose and transient adhesions are mediated by the selectin family of molecules • Selectins are receptor expressed on leukocytes and endothelium • They bind to the selectin sugars • E-selectin - endothelium • P-selectin - endothelium and Platelets • L-selectin - leukocytes

6. They are expressed at low level / absent on normal cells • They are up- regulated after stimulation by specific mediaters. • upregulated on endothelium by cytokines (TNF, IL-1) at injury sites

9. Adhesion • Rolling comes to a stop and adhesion results before leukocytes crawling between endothelial cells • The firm adhesionis mediated by molecules of immunoglobulin superfamily

10. The molecules participate are: • Endothelial: ICAM-1, VCAM-1 • Leukocyte: LFA-1, Mac-1, VLA-4 (ICAM-1 binds LFA-1/Mac-1, VCAM-1 binds VLA-4) • Ordinarily down-regulated or in an inactive conformation, but inflammation alters this • Cytokines –TNF and IL-1induce the expression of both ICAM-1 and VCAM-1

11. Leukocyte adhesion

12. Transmigration (Diapedesis) • Occurs after firm adhesion within the systemic venules and pulmonary capillaries via PECAM –1 (CD31) • Must then cross basement membrane • Leukocytes cross the BM by focally degrading them with secreted • Collagenases • Integrins

14. Early in inflammatory response mostly PMNs, • but as cytokine and chemotactic signals change with progression of inflammatory response, • alteration of endothelial cell adhesion molecule expression • activates other populations of leukocytes to adhere (monocytes, lymphocytes, etc)

15. In most acute inflammatory lesions PNL predominate in the first 6-24 hrs • Then replaced by monocytes in 24-48 hrs • Neutrophils undergo apoptosis within 24-48 hrs of exiting the blood stream

16. Leukocyte emigration(TRANSMIGRATION)

17. Chemotaxis and Activation • Leukocytes follow chemical gradient to site of injury (chemotaxis) • It is the unidirectional migration of cells towards an attractant • Soluble bacterial products • Complement components (C5a) • Cytokines (chemokine family e.g., IL-8) • LTB4 (AA metabolite)

18. Chemotactic agents bind surface receptors • inducing calcium mobilization and assembly of cytoskeletal contractile elements

19. Leukocytes: • extend pseudopods with overlying surface adhesion molecules (integrins) that bind ECM during chemotaxis • undergo activation: • Prepare AA metabolites from phospholipids • Prostaglandin (and thromboxanes) • Leukotrienes • Lipoxins

20. Prepare for degranulation and release of lysosomal enzymes (oxidative burst) • Regulate leukocyte adhesion molecule affinity as needed

21. Chemotaxis

22. Phagocytosis and Degranulation • Once at site of injury, leukocytes involve several steps: • Recognize and attach • Engulf (form phagocytic vacuole) • Kill (degrade)

23. Recognition and Binding • Recognition and attachment of leukocytes is facilitated by serum protein- opsonins • Opsonized by serum complement, immunoglobulin (C3b, Fc portion of IgG) • Corresponding receptors on leukocytes (FcR, CR1, 2, 3) leads to binding

24. Phagocytosis - Attachment