Inflamation ppt

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Inflamation ppt

  1. 1. By SROTA DAWN M.PHARM(PHARMACOLOGY) 1ST YEAR ,2ND SEM VELS SCHOOL OF PHARMACEUTICAL SCIENCES
  2. 2. • Inflammation – Protective response intended to eliminate the initial cause of cell injury and the necrotic cells and tissues arising from the injury. • Inflammation is intimately associated with the repair process which includes parenchymal cell regeneration and scarring
  3. 3. Acute Inflammation • Acute - minutes to days Chronic Inflammation • Chronic - weeks to years • Characterized by fluid and protein exudation • Lymphocytes and macrophages • PMN’s • ACUTE Inf - PMN’s (Polymorphonuclear Cells) • Exudate SG > 1.020 • CHRONIC Inf Mononuclear Cells
  4. 4. Acute inflammation “The immediate and early response to an injurious agent” Chronic inflammation “Inflammation of prolonged duration (weeks or months) in which active inflammation, tissue destruction, and attempts at repair are proceeding simultaneously“
  5. 5. Aims • • • • • Eliminate pathologic insult Remove injured tissue components Protective response Hand in hand with repair Steps: – Initiation-stimulus – Amplification: activation of cellular inflammation – Termination: Elimination
  6. 6. Five classic local signs of acute inflammation
  7. 7. 1. 2. 3. 4. 5. 6. Transient vasoconstriction Vasodilation Exudation of protein rich fluid Blood stasis Margination Emigration/Transmigration
  8. 8. • Delivery of leucocytes to the site of injury • Ingest & kill bacteria & microbes • Degrade necrotic tissues & foreign antigens • May prolong inflammation • Rarely induce tissue damage by releasing enzymes & chemical mediators, toxic radicals
  9. 9. Normal environment a
  10. 10. Inflammatory mediators
  11. 11. Increased vascular permeability › Escape of protein rich fluid into interstitium › Oedema-excess of fluid in interstitium or serous cavities › Imbalance of hydrostatic pressure  Transudate-low protein, sp gr-< 1.012 › Permeability not altered  Exudate-high protein, sp gr > 1.020 › Permeability altered  Pus –rich in polymorphs
  12. 12. Protein exits vessels :  intravascular osmotic pressure  intravascular hydrostatic pressure Endothelial gaps at intercellular junctions: * immediate transient response *histamine, bradykinin, leukotrienes, subst anceP
  13. 13. Blood pressure and plasma colloid osmotic forces in normal and inflamed microcirculation.. hydrostatic pressure (red arrows) is about 32 mm Hg Arteriole pressure is increased to 50 mm Hg 12 mm Hg 30 mm Hg. osmotic pressure of tissues is approximately 25 mm Hg (green arrows), which is equal to the mean capillary pressure osmotic pressure is reduced (averaging 20 mm Hg) because of protein leakage across the venule. The net result is an excess of extravasated fluid
  14. 14. Increased vascular permeability  Endothelial cell contraction- Immediate transient response- only venules-chem mediators  Cytoskeletal & junctional re-organization  Direct endothelial injury-Immediate sustained response-cell necrosis & detachment-All levels  Leucocyte mediated injury  Leakage from regenerating capillaries-Angiogenesis
  15. 15. Cellular events-Steps • Extravasation-Journey of the leucocytes from lumen to interstitial tissue – Margination, Rolling – Adhesion • Transmigration/ Diapedesis • Chemotaxis - Migration in interstitial tissue towards a chemical stimulus • Leucocyte activation • Phagocytosis • Release of Leucocyte products
  16. 16. Leukocyte Cellular Events • Margination and Rolling • Adhesion and Transmigration • Migration into interstitial tissue
  17. 17. Inflammation
  18. 18. Chemotaxis • Movement toward the site of injury along a chemical gradient – Chemotactic factors include • • • • Complement components (20 serum proteins) Arachadonic acid (AA) metabolites Soluble bacterial products Chemokines, cytokines
  19. 19. Leucocyte activation • Production of Arachidonic acid metabolites by DAG & increased Ca • De-granulation & secretion of lyso enzymes & activation of oxidative burst • Modulation of leucocyte adhesion molecules • Priming-Increased rate & extent of leucocyte activation
  20. 20. Phagocytosis & Degranulation • Phagocytosis (engulf and destroy) • Degranulation and the oxidative burst destroy the engulfed particle • Recognition & attachment – Opsonins coat target and bind to leukocytes • Engulfment • Killing/degradation – O2 dep: Reactive O2 species in lysosomes & EC – O2 indep: Bactericidal permeability agents, lysozyme, MBP, lactoferrin
  21. 21. Tissue injury Vasoactive mediators (eg. histamine) Production of inflammatory mediators Chemotactic factors (eg. c5a) Recruitment of inflammatory cells Increased vascular permeability Edema Acute inflammation PMNs Chronic inflammation Monos
  22. 22. Complement C5 Kinin Prekallikrein XIIa High Mol. Wt. Kininogen C3 C5 a XII C3a Kallikrein Bradykinin Plasminogen  Plasmin Fibrin  FSPs Prothrombin  Thrombin Fibrinogen Clotting Fibrinopeptides Fibrinolytic
  23. 23. • Leads to formation of bradykinin • Bradykinin causes – Increased vascular permeability – Arteriolar dilatation – Smooth muscle contraction • Bradykinin is short lived (kininases) • Vascular actions similar to histamine
  24. 24. • Role in immunity (C5-9 complex) – Membrane Attack Complex (MAC C5-9) – Punches a hole in the membrane
  25. 25. • Role in inflammation (c3a and c5a) – Vascular effects • Increase vascular permeability and vasodilation • Similar to histamine – Activates lipoxygenase pathway of arachidonic acid metabolism (c5a)
  26. 26. – Leukocyte activation, adhesion and chemotaxis (c5a) – Phagocytosis • c3b acts as opsonin and promotes phagocytosis by cells bearing receptors for c3b
  27. 27. Inflammatory Complement from Anaphylatoxins: C3a, C5a, & C4a trigger mast cells to release histamine and cause vasodilatation C5a also activates the lipoxygenase system in PMNs and monocytes  release of inflammatory mediators Leukocyte activation, adhesion, & chemotaxis: C5a activates leukocytes, promotes leukocyte binding to endothelium via integrins and is chemotactic for PMNs, monos, eos, & basos
  28. 28. Inflammatory Mediators from Complement Phagocytosis: C3b and C3bi are opsonins Control: Convertases are destabilized by "decay accelerating factor" (DAF) Inability to express DAF causes paroxysmal nocturnal hemoglobinuria C1 inhibitor (C1INH) deficiency causes hereditary angioneurotic edema
  29. 29. Vasoactive amines • Histamine – Found in mast cells, basophils and platelets – Released in response to stimuli – Promotes arteriolar dilation and venular endothelial contraction • results in widening of interendothelial cell junctions with increased vascular permeability • Serotonin – Vasoactive effects similar to histamine – Found in platelets – Released when platelets aggregate
  30. 30. Bradykinin: Potent biomolecule 1. Vasodilatation 2. Increased vascular permeability 3. Contraction of smooth muscle 4. Pain on injection 5. Short life, kininase degrades  Vascular Permeability: - Bradykinin - Fibrionopeptides - Fibrin Split Prod. Factor XII activated by: 1. Plasmin 2. Kallikrein 3. Collagen & basement membrane 4. Activated platelets 5. Co-factor = HMWK - Factor Xa - Leukotrienes
  31. 31. Arachidonic Acid (AA) • Where is it located? – AA is a component of cell membrane phospholipids • The breakdown of AA into its metabolites produces a variety of biologic effects
  32. 32. Arachidonic acid metabolites • Metabolites of AA - short-range hormones • AA metabolites act locally at site of generation • Rapidly decay or are destroyed
  33. 33. Arachidonic Acid • AA is released from the cell membrane by phospholipases which have themselves been activated by various stimuli and/or inflammatory mediators • AA metabolism occurs via two major pathways named for the enzymes that initiate the reactions; lipoxygenase and cyclooxygenase
  34. 34. AA metabolites (eicosanoids) Cyclooxygenases synthesize Prostaglandins Thromboxanes Lipoxygenases synthesize Leukotrienes Lipoxins
  35. 35. PGG2  PGI2 PGH2 TXA2 PGI2 PGD2 ; PGE2 Prostacyclin PGF2 TXA2 Thromboxane Vasodilatation Vasoconstriction Inhibits Platelet Aggregation Promotes Platelet Aggregation Vasodilatation Edema
  36. 36. Arachidonic Acid Pathways you need to know this • Lipoxygenase – 5-HETE • Chemotaxis – 5-HPETE • Leukotriene generation – Leukotrienes • Vasoconstriciton • Bronchospasm • Increased vascular permeability • Cyclooxygenase – Prostaglandins • Vasodilatation • Increased vascular permeability – Prostacyclin • Vasodilatation • Inhibits platlelet aggregation – Thromboxane A2 • Vasoconstriction • Promotes platlelet aggregation
  37. 37. Arachidonic Acid Pathways you need to know this • Lipoxygenase – 5-HETE, 5HPETE, Leukotrienes • Spasm (Vaso, Broncho) • Cyclooxygenase – Prostaglandins - EDEMA – Prostacyclin vs TXA2 • Vasodilatation vs. Vasoconstriction • Platelet aggregation Inhibits vs. promotes
  38. 38. Platelet-Activating Factor (PAF) • Another phospholipid-derived mediator released by phospholipases • Induces aggregation of platelets • Causes vasoconstriction and bronchoconstriction • 100 to 1,000 times more potent than histamine in inducing vasodilation and vascular permeability • Enhances leukocyte adhesion, chemotaxis, degranulation and the oxidative burst • It does everything!
  39. 39. Cytokines • • • • Polypeptides that are secreted by cells Act to regulate cell behaviors Autocrine, paracrine or endocrine effects These “biological response modifiers” are being actively investigated for therapeutic use in controlling the inflammatory response.
  40. 40. Lymphocyte function 1. Macrophages make IL-1 & TNF- 2. T-cells make TNF- (lymphotoxin) 3. Can be autocrine, paracrine, endocrine 4. IL-1, TNF, IL-6  acute phase responses, fever, (appetite, slow wave sleep,  circ. pmn, ACTH,  corticosteroids) 5. TNF notable for role in septic shock and maintenance of body mass (cachexia in cancer from   TNF- )
  41. 41. Nitric Oxide • • • NO is a soluble free radical gas Made by nitric oxide synthetase (NOS) in endothelium (eNOS), macrophages (iNOS), and specific neurons in the brain (nNOS) Broad range of functions and effects that are short range – – – – Vasodilatation by relaxing smooth muscle.  platelet aggregation Inhibits mast cells Regulates leukocyte recruitment

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