inflammation and repair darpan

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  • 1.INFLAMMATION AND REPAIR Darpan Nenava PG Ist year1

2. CONTENTS History Introduction Definition Types of inflammation Acute inflammation Chemical mediators Chronic inflammation Healing and repair 2 3. HISTORICAL PERSPECTIVES Earliest reference to inflammation in medical literature (1650 BC, Egypt) in the Smith Papyrus associated inflammation with heat via symbol of flame Ancient Greeks used a term which meant inflammation also indicating a hot thing The greek term persists in our word "phlegmon" used to describe internal inflammatory lesions Cornelius Celsus(1st century AD Rome):cardinal signs of inflammation redness, swelling, heat, pain 3 4. CARDINAL SIGNS OF (ACUTE) INFLAMMATION Rubor Tumor Calor Dolor= redness = swelling = heat = pain(described by Celsus 1st. Century AD) Functio laesa = loss of function (added by R. Virchow 19th Century) 5. INTRODUCTION The inflammatory response is closely intertwined with the process of repair. During repair the injurious tissue is replaced by regeneration, filling of the defect by fibrous tissue(scaring).5 6. INTRODUCTIONThe nomenclature used to describe inflammation in different tissues employs the tissue name and the suffix -itis e.gpancreatitis meningitis pericarditisarthritis 6 7. DEFINITION InflammationIt is a complex reaction to injurious agents such as microbes and damaged necrotic cells that consist of vascular response, migration and activation of leucocytes and systemic reactions.OR Inflammation is a complex reaction in tissue that consist mainly of responses of blood vessels and leukocyte7 8. TYPES OF INFLAMMATION Acute The immediate and early response to an injurious agents Min to Days1. Characterized by fluid and protein 2. PMNs 3. Exudates 4. SG >1.0208 9. TYPES OF INFLAMMATIONChronic Inflammation of prolonged duration, week or months and there is active inflammation tissue destruction, with attempts at repair are proceeding simultaneously Week to Year 1. Lymphocytes 2. Macrophages9 10. Exudates1. Increase vascular permeability 2. High protein and cell debris 3. SG > 1.020Transudate1. Normal vascular permeability 2. Low protein(mostly albumin) 3. SG < 1.02010 11. 11 12. Edema1. Exudates and transudate 2. In interstitial or in cavity12 13. Acute inflammation major components Transient vasoconstrictionVasodilatationIncrease epithelial permeabilityExtravasations of PMNs With five cardinal signs of inflammation 13 14. Acute inflammation major components14 15. Inflammatory response consist ofVascular reactionCellular reaction15 16. Vascular and cellular changes Transient vasoconstriction Vasodilatation Exudation of protein rich fluid Blood stasis Margination Emigration/ Transmigration16 17. Vascular changes Increase intravascular hydrostatic pressure Endothelial gaps in intercellular junction Fluid exits vessels Protein exits vessels Decrease intravascular osmotic pressureImmediate transient response Histamine, bradykinin, leucotrienes and substance P 17 18. Vascular changes18 19. Lewis experiment of triple response19 20. Red line appears within seconds resulting from vasodilatation of capillaries and venules Flare is a bright reddish appearance or flush surrounding the red line results from vasodilatation of the adjacent arterioles Wheal is the swelling or edema of the skin occurring from transudation of fluid in extra vascular space20 21. Vascular permeabilityVasodilatation- increase blood flow Increased intravascular hydrostatic pressureTransudate - ultra filtration of blood plasma (contain little protein, very transient just get the process started) Exudates- Protein rich with PMNs Exudates is characteristic of acute inflammation21 22. Vascular permeability Intravascular osmotic pressure decreases Osmotic pressure of interstitial fluid Outflow of water and ions edema22 23. How do endothelial cells become permeable? Gap due to Endothelial cell contraction Direct endothelial cell injury (Immediate system response)Leukocyte- dependent endothelial injury Increase transcytosis of fluid Leakage from new vessels 23 24. Gap due to Endothelial cell contraction24 25. Direct endothelial cell injury (Immediate system response)25 26. Leukocyte- dependent endothelial injury26 27. Increase transcytosis of fluid27 28. Leakage from new vessels28 29. Cellular events Margination and rolling Adhesion and transmigration Migration into interstitial tissue29 30. Selectin Weak and transient binding Results in rollingIntegrins Unregulated and activated for increase affinity to CAMS Results in firm adhesion30 31. Margination Normal flow- RBCs and WBCs flow in the center of the vessels. A cell poor plasma is flowing adjacent to endothelium As blood flows slow WBCs collect along the endothelium Margination31 32. Endothelium activationThe underlying stimuli causes release of mediators Activate the endothelium causing selectin and other mediators to be moved quickly to the surface32 33. Four families of adhesion molecules are involved in leukocyte migration Selectins E-selectin (on endothelium) P-selectin (on endothelium & platelets; is preformed and stored in Weible Palade bodies) L-selectin (leukocytes) Ligands for E-and P-Selectins are sialylated glycoproteins (e.g Sialylated Lewis X)Ligands for L-Selectin are Glycanbearing molecules such as GlyCam-1, CD34, MadCam-1Integrins (a + b chain) Heterodimeric molecules VLA-4 (b1 integrin) binds to VCAM-1 LFA1 and MAC1 (CD11/CD18) = b2 integrin bind to ICAM Expressed on leukocytesImmunoglobulin family ICAM-1 (intercellular adhesion molecule 1)Mucin-like glycoproteinsHeparan sulfate (endothelium)VCAM-1 (vascular adhesion molecule 1)Ligands for CD44 on leukocytesAre expressed on activated endotheliumBind chemokinesLigands are integrins on leukocytes 33 34. Rolling and AdhesionSelectin transiently binds to the receptors PMNs bounces or roll along the endothelium Mediated by integrins ICAM-1 and VCAM-134 35. TRANSMIGRATIONCHEMOTAXIS Mediated/assisted by VCAM 1 Movements towards the site of injury along a chemical and ICAM 1(integrins) gradient Chemotactic factor include Diapedesis (cell crawling) 1. Components (20 serum protien) Primary in venules 2. Arachadonic acid metabolites Collagenase degrade 3. Soluble bacterial products basement membrane 4. Chemokines 5. Cytokines Increase permeability35 36. Selectin sIntegrins36 37. Inflammatory Cells The circulating cells includes Neutrophils Monocytes Eosinophils Lymphocytes Basophils Platelets The connective tissue cells are Mast cells Fibroblast Macrophages Lymphocytes 37 38. Inflammatory Cells38 39. Phagocytosis and degranulation Involves three sequential steps1. Recognition and attachment of the particle to be ingested by leucocytes 2. Phagocytosis (engulf and destroys ) 3. Killing/degranulation oxygen dependent :reactive O2 species in Lysosomes Oxygen independent- bacterial permeability agents , Lysosomes , lactoferin 39 40. Leukocyte express several receptors that recognize external stimuli and deliver activating signals Mannose Receptor Receptors for microbial products-toll like receptors(TLRs) G protein-coupled receptors Receptors for opsonins Receptors for cytokines 40 41. 41 42. EngulfmentAfter particle is bound to phagocyte receptors, extension of cytoplasm(pseudopods flows around it) Plasma membrane pinches offForms a vesicle enclosing particle Phagosome fuses to lysosomal granules Killing of microbes by lysosomal enzymes in phago Lysosomes 42 43. 43 44. KILLING AND DEGRANULATION Final step Microbial killing is accomplished largely by reactive oxygen species(ROS)also called as reactive oxygen intermediates And reactive nitrogen species mainly derived from NO44 45. Chemical mediators in inflammationPlasma derived-circulating precursors have to be activated Cell derived-sequestered intracellularly synthesized de novo Most mediators bind to receptors on cell surface but some have direct enzymatic or toxic activity. Mediators are tightly regulated45 46. 46 47. Mediators in acute inflammation47 48. Plasma derived mediators Complement Kinin Clotting Fibrinolytic48 49. 49 50. Cell derived mediators-Vasoactive amines Histamine 1. Found in mast cells , basophils and platelets 2. Release in response to stimuli 3. Promotes arterioles dilation and venules endothelial contraction 4. Results in widening of inter-endothelial cell junction with increase in vascular permeability50 51. Serotonin/5 hydroxytryptamine-1. Vaso-active effects similar to histamine but less potent 2. Found in chromaffin cells of GIT, spleen, nervous system, mast cells and platelets 3. Release when platelet aggregation51 52. BradykininPotent bio-molecule 1. Vasodilatation2. Increase vascular permeability 3. Contraction of smooth muscle4. Short life52 53. Arachodonic acid/eicosanoids AA is component of cell membrane phospholipids AA is activated by some stimuli or mediators like C5a so as to form AA metabolitesMetabolites of AA short range hormone Acts locally at the site of generation Rapidly decay or destroys 53 54. AA metabolites occurs by two major pathways named for the enzymes that initiates the reaction, lypoxygenase and cycloxygenase Cycloxygense synthesize-prostaglandin, thromboxane Lypoxygenase synthesize- leucotrines and lipoxins54 55. Cycloxygense pathway Cycloxygense is a fatty acid enzyme act on activated AA to form prostaglandin which further activated by enzyme to form3 metabolitesProstaglandin-Increase vascular permeability, vasodilatation, inhibit inflammatory cell function Prostacyclin- Vasodilatation and inhibits platelet aggregationThromboxane A2-Vasoconstriction,broncoconstriction, enhances inflammatory cell function Promotes platelet aggregation 55 56. Lipoxygenase pathway Enzyme lypoxygenase acts an activator to AA to form 5-HETE (hydroperoxy eico-astetraeonic acid) which on further per oxidation forms 2 metabolites Leucotrines Lipoxins Causes VasoconstrictionBronchospasm Increase vascular permeability 56 57. 57 58. AA metabolites Participat

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