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Inflammation 4

Designed for UG pathology teaching.

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Inflammation 4

  1. 1. Inflammationand Repair - 4 Dr.CSBR.Prasad, M.D. v3-CSBRP-May-2012
  2. 2. Recognition of Microbes and Dead Tissues 3Rs • Recruitment • Recognition • Removal v3-CSBRP-May-2012
  3. 3. Recognition of Microbes and Dead TissuesLeukocytes express several receptors that recognize external stimuli and deliver activating signal v3-CSBRP-May-2012
  4. 4. v3-CSBRP-May-2012
  5. 5. v3-CSBRP-May-2012
  6. 6. v3-CSBRP-May-2012
  7. 7. Recognition of Microbes and Dead Tissues Leukocyte – Receptors: 1. Toll-like receptors (TLRs) 2. G protein – coupled receptors 3. Receptors for opsonins 4. Receptors for cytokines v3-CSBRP-May-2012
  8. 8. Recognition of Microbes and Dead TissuesLeukocyte – Receptors: 1. Toll-like receptors (TLRs) Bind microbial products 10 mammalian TLRs have been identified Mediate cellular responses to bacterial products LPS / Endotoxin Bacterial proteoglycans Lipids Unmethylated CpG nucleotides (abundant in bacteria / viruses) Function through receptor-associated kinases to stimulate the production of microbicidal substances and cytokines by the v3-CSBRP-May-2012 leukocytes
  9. 9. Recognition of Microbes and Dead TissuesLeukocyte – Receptors: 1. Toll-like receptors (TLRs) 2. G protein–coupled receptors Found on neutrophils, macrophages Recognize: Bacterial peptides with N-formylmethionyl residues Chemokines Products of complement such as C5a Lipid mediators [PAF, PGs, and LTs] Ligand binding induces Extravasation Production of microbicidal substances (ROS). v3-CSBRP-May-2012
  10. 10. Recognition of Microbes and Dead TissuesLeukocyte – Receptors: 1. Toll-like receptors (TLRs) 2. G protein–coupled receptors 3. Receptors for opsonins: Leukocytes express receptors for proteins that coat microbes Opsonins include: Ig, C, and lectins Phagocytes have: • FcγRI (for Fc fragment) • CR1 (for C3b) • Receptor for plasma Lectins [mannan-binding lectin] Receptors promotes phagocytosis v3-CSBRP-May-2012
  11. 11. Receptors for opsonins v3-CSBRP-May-2012
  12. 12. Recognition of Microbes and Dead TissuesLeukocyte – Receptors: 1. Toll-like receptors (TLRs) 2. G protein–coupled receptors 3. Receptors for opsonins 4. Receptors for cytokines: Leukocytes express receptors for cytokines Interferon-γ (IFN-γ) IFN-γ is the major macrophage-activating cytokine v3-CSBRP-May-2012
  13. 13. v3-CSBRP-May-2012
  14. 14. Removal of the Offending Agents v3-CSBRP-May-2012
  15. 15. Removal of the Offending Agents1. Recognition of microbes by the receptors2. Leukocyte activation: o Increase in cytosolic Ca2+ & o Activation of enzymes:  Protein kinase C and  Phospholipase A21. Destruction of microbes o Phagocytosis and o Intracellular killing v3-CSBRP-May-2012
  16. 16. Killing & Degradation• Antibacterial substances kill the bacteria• Killed bacteria are degraded by the hydrolytic enzymes• These mechanisms may not degrade some eg: Myc.TB v3-CSBRP-May-2012
  17. 17. Killing & DegradationFollowing mechanisms facilitate this process:A. INTRACELLULAR Mechanisms: 1. Oxidative – by free radicals of O2 i. MPO-dependednt ii. MPO-independent 2. Oxidative – by lysosomal granules 3. Non-oxidative mechanismsB. EXTRA CELLULAR Mechanisms v3-CSBRP-May-2012
  18. 18. Killing & DegradationFollowing mechanisms facilitate this process:A. INTRACELLULAR Mechanisms: 1. Oxidative – by free radicals of O2 • This mechanism produces reactive O2 metabolites (O.2, H2O2, OH., HOCl, HOI, HOBr) • Respiratory burst by activated leucocytes requires presence of NADPH oxidase • Liberation of superoxide anion O.2 v3-CSBRP-May-2012
  19. 19. v3-CSBRP-May-2012
  20. 20. Superoxide is subsequentlyconverted into H2O2 which has bactericidal properties v3-CSBRP-May-2012
  21. 21. . Superoxide radicals O 2 are utilized in MPO-dependentand MPO-independent killing v3-CSBRP-May-2012
  22. 22. MPO-dependent killingH2O2-MPO halide system v3-CSBRP-May-2012
  23. 23. v3-CSBRP-May-2012
  24. 24. Killing & DegradationFollowing mechanisms facilitate this process:A. INTRACELLULAR Mechanisms: 1. Oxidative – by free radicals of O2 i. MPO-dependednt ii. MPO-independent 2. Oxidative – by lysosomal granules 3. Non-oxidative mechanismsB. EXTRA CELLULAR Mechanisms v3-CSBRP-May-2012
  25. 25. Killing & Degradation Oxidative – by Lysosomal granules• The preformed lysosomal granules discharged into the phagosomes• They inlcude proteases, trypsinase, phospholipase and ALP• This induces proteolysis v3-CSBRP-May-2012
  26. 26. Killing & DegradationFollowing mechanisms facilitate this process:A. INTRACELLULAR Mechanisms: 1. Oxidative – by free radicals of O2 i. MPO-dependednt ii. MPO-independent 2. Oxidative – by lysosomal granules 3. Non-oxidative mechanismsB. EXTRA CELLULAR Mechanisms v3-CSBRP-May-2012
  27. 27. Killing & DegradationNon-oxidative mechanisms(do not require oxygen for bactericidal activity)Include the following:1. Granules:  lysosomal hydrolases, cationic proteins, lipases, DNAses  These enzymes cause lysis with in phagosome1. Nitric oxide:  Formed by nitric oxide synthase  Similar to ROS in their action  Potent microbial killers  Produced by endothelial cells and by activated macrophages v3-CSBRP-May-2012
  28. 28. Killing & DegradationONOO. damages the lipids, proteins, and nucleic acids v3-CSBRP-May-2012
  29. 29. v3-CSBRP-May-2012
  30. 30. Killing & DegradationFollowing mechanisms facilitate this process:A. INTRACELLULAR Mechanisms: 1. Oxidative – by free radicals of O2 i. MPO-dependednt ii. MPO-independent 2. Oxidative – by lysosomal granules 3. Non-oxidative mechanismsB. EXTRA CELLULAR Mechanisms v3-CSBRP-May-2012
  31. 31. Killing & DegradationEXTRA CELLULAR Mechanisms:Immune mechanisms o Ab mediated lysis o Cell mediated cytotoxicity v3-CSBRP-May-2012
  32. 32. Is inflammationalways protective? v3-CSBRP-May-2012
  33. 33. Release of Leukocyte Products andLeukocyte-Mediated Tissue Injury v3-CSBRP-May-2012
  34. 34. Release of Leukocyte Products andLeukocyte-Mediated Tissue Injury• Normal tissue is also damaged in some inflammatory processes• These mechanisms are similar to antimicrobial defense• Once the leukocytes are activated, their efector mechanisms do not distinguish between offender and host v3-CSBRP-May-2012
  35. 35. Release of Leukocyte Products andLeukocyte-Mediated Tissue Injury• Collateral damage is more common in TB, Leprosy and viral infections• Inflammatory responses to self Ags – Autoimmunity• Excessive reaction to harmless environmental substances may result in Allergic diseases eg: asthma v3-CSBRP-May-2012
  36. 36. Clinical Examples of Leukocyte-Induced InjuryDisorder Cells & molecules involvedACUTEARDS NeutrophilsTransplant Rejection Lymphocytes, Abs, CAsthma EøGlomerulonephritis PMNs, Mø, C, AbsSeptic shock CytokinesCHRONICArthritis Lymphocytes, macrophages; AbsAtherosclerosis Macrophages, LymphocytesPulmonary fibrosis Macrophages, Fibroblasts v3-CSBRP-May-2012
  37. 37. Mechanisms of entry of lysosomalcontents into the extracellular milieu• Frustrated phagocytosis• Phagocytosis of membrane-damaging substances• Premature release of lysozymes before the formation of phagosome v3-CSBRP-May-2012
  38. 38. Mechanisms of entry of lysosomalcontents into the extracellular milieu Premature release of lysozymes before the formation of phagosome v3-CSBRP-May-2012
  39. 39. Defects in Leukocyte Function v3-CSBRP-May-2012
  40. 40. Defects in Leukocyte Function• Inherited defects in leukocyte adhesion – LAD• Inherited defects in phagolysosome function – Chédiak-Higashi syndrome• Inherited defects in microbicidal activity – Chronic granulomatous disease• Acquired deficiencies – Cancer chemotherapy v3-CSBRP-May-2012
  41. 41. Disease DefectGENETICLAD Defective adhesion moleculesCGD Decreased oxidative burstMPO deficiency defective MPO—H2O2 systemChédiak-Higashi syndrome Lysosomal membraneACQUIREDBone marrow suppression: Production of leukocytestumors, radiation, andchemotherapyDiabetes, malignancy, sepsis, Adhesion and chemotaxischronic dialysisLeukemia, anemia, sepsis, Phagocytosis and microbicidaldiabetes, malnutrition activity v3-CSBRP-May-2012
  42. 42. Chediak-Higashi Syndromev3-CSBRP-May-2012
  43. 43. ENDv3-CSBRP-May-2012
  44. 44. Laboratory Findings in Inflammation v3-CSBRP-May-2012
  45. 45. Complete Blood Count (CBC)Total RBCTotal WBC Hemoglobing(HB) Hematocrit(HCT)RBC Indices: MCV,MCH,MCHC WBC Differential v3-CSBRP-May-2012
  46. 46. Laboratory Findings in Inflammation Leukocytosis :15,000-20,000 cells/ul (4,000-10,000 cells/ul)Leukemoid reaction:40,000-100,000 cells/ul v3-CSBRP-May-2012
  47. 47. Laboratory Findings in Inflammation“Left Shift”: an increase in the number of immature neutrophilsImmature neutrophils: Bands or stabs Meta or Juvenile Myleocyte v3-CSBRP-May-2012
  48. 48. “Left Shift” Normal 1 2 1 3 70 20 3Baso Eos Meta Stabs Segs Lymph Mono 0 1 3 12 75 8 1 Left Shift v3-CSBRP-May-2012
  49. 49. Laboratory Findings in Inflammation Neutrophilia : bacterial Lymphocytosis : viral Leukopenia:many virusesEosinophilia: parasites & allergies v3-CSBRP-May-2012
  50. 50. Laboratory Findings in InflammationErythrocyte Sedimentation Rate (ESR) will be increased v3-CSBRP-May-2012
  51. 51. Erythrocyte Sedimentation Rate (ESR) 0 0 10 The distance, in mm, 10 the RBC fall in 1 hr 20 20 is the Sed Rate 30 1hr 30 40 40 50 mm 50 mm 60 60 70 70 80 80 90 90 100 v3-CSBRP-May-2012 100
  52. 52. Acute Phase Proteins During an inflammatory response anumber of interleukins(IL) are producedIL-6 stimulates the hepatic production ofa number of proteins ,called acute phase proteins v3-CSBRP-May-2012
  53. 53. Acute Phase Proteins Fibrinogen C-Reactive Protein (CRP) C3 C4 Ceruloplasmin v3-CSBRP-May-2012
  54. 54. Acute Phase ProteinsAcute Phase Proteins are normally found in the blood at low concentrations, but following hepatic stimulation by IL-6 their concentration increases Detection of elevated levels of acute phase proteins is an indication of an inflammatory response v3-CSBRP-May-2012
  55. 55. v3-CSBRP-May-2012
  56. 56. Ligands• In biochemistry and pharmacology, a ligand (Latin ligare = to bind) is a substance that is able to bind to and form a complex with a biomolecule to serve a biological purpose.• In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.• The binding occurs by intermolecular forces, such as ionic bonds, hydrogen bonds and Van der Waals forces. The docking (association) is usually reversible (dissociation). Actual irreversible covalent binding between a ligand and its target molecule is rare in biological systems. In contrast to the meaning in metalorganic and inorganic chemistry, it is irrelevant whether the ligand actually binds at a metal site, as it is the case in hemoglobin.• Ligand binding to a receptor alters the chemical conformation, that is the three dimensional shape of the receptor protein. The conformational state of a receptor protein determines the functional state of a receptor. Ligands include substrates, inhibitors, activators, and neurotransmitters. The tendency or strength of binding is called affinity.• Radioligands are radioisotope labeled compounds and used in vivo as tracers in PET studies and for in vitro . v3-CSBRP-May-2012
  57. 57. The movement of leucocytes from out of the blood vessels into the tissues spaces is known as DIAPEDESIS WOW! v3-CSBRP-May-2012
  58. 58. MPO-independent killing . O2 ++ Fe (Hydroxyl radical) v3-CSBRP-May-2012

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