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  1. 1. INFLAMMATION II Cellular Events
  2. 2. The cellular exudate <ul><li>First exudation of fluid, later leukocytes </li></ul><ul><li>Exudation of leukocytes </li></ul><ul><li>A. Adhesion </li></ul><ul><li>B. Emigration </li></ul><ul><li>C. Chemotaxis </li></ul><ul><li>Phagocytosis </li></ul>
  3. 3. A. Adhesion <ul><li>Normal axial flow – leukocytes + RBCs, cell free plasma </li></ul><ul><li>Slowing or stasis -> widening of central stream of cells, narrowing of plasma zone (loss by exudation) </li></ul><ul><li>White cells impinge upon the endothelium which is sticky and line the endothelial surface (margination of WBCs/pavementation of the endothelium) </li></ul>
  4. 5. Adhesion( contd) <ul><li>Leukocyte adhesion molecules – glycoproteins LFA – 1,MO – 1,&p150,95 on the surface of cells </li></ul><ul><li>Chemical mediator C5a & Leukotreine B4 (LTB4) </li></ul><ul><li>Endothelial cell receptors stimulated by mediators – endotoxin & interleukin 1 (IL-1), endothelial leukocyte adhesion molecule – 1 (ELAM-1) </li></ul><ul><li>Intracellular adhesion molecule (ICAM-1) serves as receptor for LFA-1 adhesion molecule on poly, mono, & lymphocytes </li></ul>
  5. 6. B. Emigration <ul><li>Adherent leukocytes > pseudopodia </li></ul><ul><li>↓ </li></ul><ul><li>between 2 endothelial cells </li></ul><ul><li>↓ </li></ul><ul><li>Basement memb.& perivascular sheath (damaged by collagenases & proteases on surface of migrating cells) </li></ul><ul><li>First cells involved PMN – 1st 24 hrs </li></ul><ul><li>-> Monocytes/macrophages – next 24 hrs followed by lymphocytes & RBCs – follow by diapedesis. </li></ul>
  6. 7. C. Chemotaxis <ul><li>The directional movement of an organism in response to a chemical gradient is chemotaxis </li></ul><ul><li>Boyden`s chamber experiment </li></ul>
  7. 9. Chemotactic facors for leukocytes <ul><li>Leukotriene B4 (LTB4) </li></ul><ul><li>Platelet activating factor (PAF) </li></ul><ul><li>Components of complement system – C5a </li></ul><ul><li>Cytokines( IL8 ) </li></ul><ul><li>Soluble bact. products (formylated peptides) </li></ul><ul><li>Monocyte chemoattractant protein (MCP-1) </li></ul><ul><li>Chemotactic factor for CD4 & Tcells </li></ul><ul><li>Eosinophil chemotactic factor of anaphylaxis (ECF – A) </li></ul>
  8. 10. Chemotactic factors <ul><li>Induce leukocyte activation also </li></ul><ul><li>↓ </li></ul><ul><li>- Production of arachidonic acid metabolites </li></ul><ul><li>-degranulation-> lysosomal enzymes </li></ul><ul><li>-generation of O2 metabolites </li></ul><ul><li>- ↑ intracellular Ca </li></ul><ul><li>-↑ in leukocyte surface adhesion molecules </li></ul>
  9. 11. Phagocytosis <ul><li>Process of engulfment of solid particulate material by the cells. </li></ul><ul><li>Cells ( phagocytes) – </li></ul><ul><li>1.PMNs (early ac. Inflammation) </li></ul><ul><li>2.Circulating monocytes and fixed tissue mononuclear phagocytes - macrophages </li></ul>
  10. 13. Phagocytosis (contd.) <ul><li>Energy for phagocytosis from anaerobic glycolysis </li></ul><ul><li>Phagocytosis -> series of metabolic events (Respiratory burst) </li></ul><ul><li>- ↑utilisation of glucose through hexose monophosphate shunt -> result release of powerful oxidising agents – superoxide radical O2&H2O2 -> intracellular destruction of bacteria </li></ul><ul><li>Surface phagocytosis – fibrin network >trapping of org. by PNMs without prior opsonisation </li></ul>
  11. 14. Phagocytosis <ul><li>4 steps </li></ul><ul><li>Attachment stage ( opsonisation) </li></ul><ul><li>Engulfment stage </li></ul><ul><li>Secretion ( degranulation stage) </li></ul><ul><li>Killing or degradation stage </li></ul>
  12. 15. Attachment stage <ul><li>Phagocytes & micro- org > -vely charged particles > repel each other </li></ul><ul><li>Opsonins (naturally occuring substances in serum) </li></ul><ul><li>- IgG opsonin + receptor on the surface of phagocyte (Fc fragment) </li></ul><ul><li>- C3b opsonin + corresponding receptor on the phagocyte </li></ul>
  13. 16. Engulfment stage <ul><li>Pseudopods around the particle ->Phagocytic vacuole->breaks from cell surface& lies free in cell cytoplasm. </li></ul><ul><li>PV+lysosomes fuse ->Phagolysosome/ </li></ul><ul><li>Phagosome. </li></ul>
  14. 18. SECRETION(DEGRANULATION STAGE ) <ul><li>Preformed granule ->discharged into phagosome </li></ul><ul><li>Specific granules fuse first- liberate </li></ul><ul><li>Lysozyme,lactoferrin&alk.PO4ase. </li></ul><ul><li>Later azurophilic granules fuse->release lysosomal enzymes &PNM ->degranulated </li></ul>
  15. 20. SECRETION.contd <ul><li>Mononuclears synthesise & secrete enzymes( interleukins 2&6,TNF->(act as pyrogens->fever)) </li></ul><ul><li>-arachidonic acid metabolites (prostaglandins,leukotrienes, PAF)& </li></ul><ul><li>O2metabolites(superoxideO2,H2O2, </li></ul><ul><li>hypochlorous acid.) </li></ul>
  16. 21. KILLING or DEGRADATION STAGE <ul><li>MICRO-ORGANISMS KILLED BY ANTIBACTERIAL SUBS ARE DEGRADED BY HYDROLYTIC ENZYMES </li></ul><ul><li>ANTIBACTERIAL AGENTS ACT BY- </li></ul><ul><li>1. O2 dependent bactericidal mech.(by prodn. Of reactive O2 metabolites ->(eliminate micro-org. growing within phagocytes )) </li></ul><ul><li>2.O2 independent bactericidal mech.- </li></ul><ul><li>(lysosomal hydrolases, permeability increasing factors,defensins,cationic proteins) </li></ul><ul><li>3.Nitric acid mech. In exptal animals- fungicidal & antiparasitic action. </li></ul>
  17. 22. Activities of PMN in Ac. Infln. <ul><li>RANDOM MOVT. </li></ul><ul><li>CHEMOTAXIS </li></ul><ul><li>ADHERENCE TO BACTERIA & PARTICLES </li></ul><ul><li>PHAGOCYTOSIS </li></ul><ul><li>ACTIVATION OF HEXOSE MONOPHOSPHATE SHUNT </li></ul><ul><li>BACTERICIDAL ACTIVITY </li></ul><ul><li>DEFECT IN ANY OF THESE MECH. ->↓RESISTANCE TO INFN. </li></ul>
  18. 23. Local sequelae of ac. Infln. <ul><li>Changes following ac. Infln. Depends on : </li></ul><ul><li>1. the amount of tissue damage </li></ul><ul><li>2. whether or not the causative agent remains. </li></ul><ul><li>Some agents -> destruction of fixed tissues. If pt. survives,1.autolysis of the area> macrophages infiltrate-> healing by repair & regeneration 2.digestion of the area by lysosomal enzymes of PMN (pus cells) -> abscess. </li></ul><ul><li>If no tissue death,- PMN -> mononuclears -> onset of demolition phase </li></ul>
  19. 24. Demolition phase <ul><li>Macrophages (scavengers) engulf-fibrin,red cells ,pus cells, foreign materials, bacteria. </li></ul><ul><li>- fuse to produce giant cells </li></ul><ul><li>- act best when activated ( MAF identical to Interferon gamma)↓ </li></ul><ul><li>bacterial endotoxins </li></ul><ul><li>phagocytose bacteria </li></ul>
  20. 25. Functions of macrophages <ul><li>Antimicrobial defence </li></ul><ul><li>Immunological functions </li></ul><ul><li>Cellular immunity </li></ul><ul><li>Antitumor activity </li></ul><ul><li>Control of granulopoiesis </li></ul><ul><li>Control of erythropoiesis </li></ul><ul><li>Secrtory activity ->lysosomal enzymes, lysozyme,plasminogen activators & inhibitors,collagenases, elastase, complement components,prostaglandins,leukotriens </li></ul>
  21. 26. End results <ul><li>Resolution – complete return to normal </li></ul><ul><li>Demolition phase -> removal of exudate – resolution </li></ul><ul><li>Removal of exudate delayed – fibrin invaded by granulation tissue (organisation) – heals by fibrosis </li></ul>
  22. 27. End results(Contd.) <ul><li>2. Suppuration </li></ul><ul><li>Infl. reaction associated with necrosis -> suppuration </li></ul><ul><li>Necrotic material > softening > fluid pus in a cavity > abscess </li></ul><ul><li>Pus – dead & dying leukocytes </li></ul><ul><li>-- other components of infl. (oedema fluid,fibrin) </li></ul><ul><li>--organisms (many living – culture) </li></ul><ul><li>-- tissue debris (nucleic acids & lipids) </li></ul><ul><li>Epithelial surface involved > ulcer-- floor ->necrotic tissue,ac. Infl. exudate(slough)↓ </li></ul><ul><li>gets detached– heals by repair &regeneration. </li></ul><ul><li>Abscess > drained /not drained ↓ </li></ul><ul><li>dense fibrous tissue,watery content absorbed,calcification. </li></ul>