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Inflammation 8


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Inflammation 8

  1. 1. Inflammationand Repair - 8 Dr.CSBR.Prasad, M.D. v3-CSBRP-May-2012
  2. 2. Tissue renewal Regeneration and Repair v3-CSBRP-May-2012
  3. 3. RegenerationRegeneration refers to the proliferation of cells and tissues to replace lost structures Whole organs and complex tissues rarely regenerate after injury Exceptions are liver, epithelia of GIT, Skin, Hemopoietic tissue Compensatory growth Vs Regeneration v3-CSBRP-May-2012
  4. 4. Repair Repair is a healing process It’s a combination of regeneration and scar formation v3-CSBRP-May-2012
  5. 5. RepairTissue repair depends on:  the ability of the tissue to regenerate and  the extent of the injury v3-CSBRP-May-2012
  6. 6. Repair Chronic inflammation > growth factors and cytokines > Scar FIBROSIS is used to describe the extensive deposition of collagen v3-CSBRP-May-2012
  7. 7. RepairECM components are essential for wound healing:  Provide the framework for cell migration  Facilitate Angiogenesis  Cells in the ECM produce growth factors v3-CSBRP-May-2012
  8. 8. RepairAlthough repair is a healing process, it may cause tissue dysfunction v3-CSBRP-May-2012
  9. 9. RepairAlthough repair is a healing process, it may causetissue dysfunctionExamples: • Intestinal strictures• AS • Adhesions after• Healed MI surgery• Cirrhosis • Ankylosis• Contractures • Cranial nerve palsies after TB-meningitis• Corneal opacities• Pulmonary fibrosis• Bronchiectasis v3-CSBRP-May-2012
  10. 10. Cirrhosis of liver v3-CSBRP-May-2012
  11. 11. Pulmonary fibrosis v3-CSBRP-May-2012
  12. 12. v3-CSBRP-May-2012
  13. 13. v3-CSBRP-May-2012
  14. 14. Basal Meningitis - TB v3-CSBRP-May-2012
  15. 15. 6th left cranial nerve plasy v3-CSBRP-May-2012
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  20. 20. Ocular Herpes v3-CSBRP-May-2012
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  22. 22. Understanding the mechanisms of regenerationand repair requires: •knowledge of the control of cell proliferation •signal transduction pathways, and •functions of ECM components v3-CSBRP-May-2012
  23. 23. Principles of cell proliferationControl of Normal Cell Proliferation and Tissue Growth• In adult tissues the size of cell populations is determined by the rates of cell proliferation, differentiation, and death by apoptosis• Cell proliferation can be stimulated by physiologic and pathologic conditions v3-CSBRP-May-2012
  24. 24. Principles of cell proliferationControl of Normal Cell Proliferation and Tissue GrowthCell proliferation can be stimulated by physiologicand pathologic conditionsPhysiological: Pathological:EM to Estrogen • NPH toThyroid to TSH, dihydrotestosterone pregnancy • Nodular goitres to TSH v3-CSBRP-May-2012
  25. 25. Why thyroid enlarges in pregnancy?α-chain of HCG is identical to the α-chain of TSH v3-CSBRP-May-2012
  26. 26. Principles of cell proliferation Cell proliferation is largely controlled by signals(soluble or contact-dependent) from themicroenvironment that either stimulate or inhibitproliferation An excess of stimulators or a deficiency ofinhibitors leads to net growth and, in the case ofcancer, uncontrolled growth v3-CSBRP-May-2012
  27. 27. TISSUE PROLIFERATIVE ACTIVITYThe tissues of the body are divided into three groups on the basis of the proliferative activity of their cells:1. Continuously dividing (labile tissues)2. Quiescent (stable tissues) and3. Nondividing (permanent tissues) v3-CSBRP-May-2012
  28. 28. TISSUE PROLIFERATIVE ACTIVITY1. Continuously dividing (labile tissues)Cells proliferate throughout life, replacing those that are destroyedExamples include:Surface epithelia, such as stratified squamous epithelia of the skin, oral cavity, vagina, and cervix; the lining mucosa of all the excretory ducts of the glands of the body (e.g., salivary glands, pancreas, biliary tract)The columnar epithelium of the GI tract and uterus; the transitional epithelium of the urinary tractCells of the bone marrow and hematopoietic tissuesIn most of these tissues mature cells are derived from adult stem cells, which have a tremendous capacity to proliferate v3-CSBRP-May-2012
  29. 29. TISSUE PROLIFERATIVE ACTIVITY1. Continuously dividing (labile tissues)2. Quiescent (stable tissues) Have a low level of replication Can undergo rapid division in response to stimuliExamples: Parenchymal cells of liver, kidneys, and pancreas Mesenchymal cells such as fibroblasts and smooth muscle Vascular endothelial cells and Lymphocytes and other leukocytes v3-CSBRP-May-2012
  30. 30. TISSUE PROLIFERATIVE ACTIVITY1. Continuously dividing (labile tissues)2. Quiescent (stable tissues)3. Nondividing (permanent tissues)Cells that have left the cell cycleCannot undergo mitotic divisionExamples:• Neurons• Skeletal and• Cardiac muscle cellsGliosisCardiac muscle has very limited regenerative capacity v3-CSBRP-May-2012
  31. 31. v3-CSBRP-May-2012
  32. 32. Role of the extracellularmatrix in regenerationand repair:Liver regeneration withrestoration of normaltissue after injury requiresan intact cellular matrix. Ifthe matrix is damaged theinjury is repaired byfibrous tissue depositionand scar formation v3-CSBRP-May-2012
  33. 33. STEM CELLS• Stem cells are characterized by their self- renewal properties and by their capacity to generate differentiated cell lineages v3-CSBRP-May-2012
  34. 34. Stem cellsMaintainance of stem cells is achieved by two mechanisms:1. Obligatory asymmetric replication  with each cell division, one of the daughter cells retains its self-renewing capacity while the other enters a differentiation pathway2. Stochastic differentiation:  cell division may generate either two self- renewing stem cells or two cells that will differentiate v3-CSBRP-May-2012
  35. 35. v3-CSBRP-May-2012
  36. 36. Termso Pluripotent stem cells: can generate all tissues of the bodyo Multipotent stem cells: which have more restricted developmental potential, and eventually produce differentiated cells from the three embryonic layerso Transdifferentiation: indicates a change in the lineage commitment of a stem cello Adult stem cells or somatic stem cells: have a more restricted capacity to generate different cell types have been identified in many tissueso Induced pluripotent stem cells: differentiated cells of humans can be reprogrammed into pluripotent cells, similar to ES cells, by the transduction of genes encoding ES cell transcription factor v3-CSBRP-May-2012
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  38. 38. Reprogramming of Differentiated Cells: Induced Pluripotent Stem Cells• Transfer the nucleus to an enucleated oocyte.• The oocytes implanted into a surrogate mother• This can generate cloned embryos that develop into complete animals• This procedure, known as reproductive cloning,• therapeutic cloning:In this technique the nucleus of a skin fibroblast from a patient is introduced into an enucleated human oocyte to generate ES cells, which are kept in culture, and then induced to differentiate into various cell types.• These cells are inefficient and often inaccurate. One of the main reasons for the inaccuracy is the deficiency in histone methylation in reprogrammed ES cells, which results in improper gene expression. v3-CSBRP-May-2012
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  40. 40. LIVER REGENERATIONHepatocyte proliferation in the regenerating liver is triggered by the combined actions of cytokines and polypeptide growth factors – Priming phase – TNF, IL-6 & C – system – DNA synthesis – HGF, TGFα, and HB-EGF – Adjuvants - Norepinephrine, serotonin, insulin, thyroxin and growth hormone v3-CSBRP-May-2012
  41. 41. • Individual hepatocytes replicate once or twice during regeneration and then return to quiescence• Growth inhibitors, such as TGF-β and activins, may be involved in terminating hepatocyte replication• Intrahepatic stem or progenitor cells do not play a role in the compensatory growth that occurs after partial hepatectomy• Endothelial cells and other nonparenchymal cells in the regenerating liver may originate from bone marrow precursors v3-CSBRP-May-2012
  42. 42. v3-CSBRP-May-2012
  43. 43. Extracellular Matrix and Cell-Matrix InteractionsTissue repair and regeneration depends on:• Cytokines• Interactions between cells & ECMThe ECM regulates the growth, proliferation, movement, and differentiation of the cells living within it v3-CSBRP-May-2012
  44. 44. ECM - various functions• Mechanical support• Control of cell growth• Maintenance of cell differentiation• Scaffolding for tissue renewal• Establishment of tissue microenvironments• Storage and presentation of regulatory molecules v3-CSBRP-May-2012
  45. 45. ECM - CompositionThe ECM is composed of three groups of macromolecules: Fibrous structural proteins - provide tensile strength Adhesive glycoproteins: connect the matrix elements to one another and to cells Proteoglycans and hyaluronan - resilience v3-CSBRP-May-2012
  46. 46. Mechanisms by which ECM components and growth factors interact and activate signaling pathways v3-CSBRP-May-2012
  47. 47. Angiogenesis by mobilization of endothelial precursor cells (EPCs) from the bone marrow and from preexisting vessels (capillary growth) v3-CSBRP-May-2012
  48. 48. Main components of theextracellular matrix (ECM) v3-CSBRP-May-2012
  49. 49. Healing by Repair,Scar Formation and Fibrosis v3-CSBRP-May-2012
  50. 50. Healing by Repair, Scar Formation and FibrosisRepair occurs by fibrosis & scar formation when:• There is loss of parenchyma & frame workHere lost tissue will be replaced by collagen v3-CSBRP-May-2012
  51. 51. Repair by connective tissue deposition includes the following basic features:• Inflammation• Angiogenesis• Migration and proliferation of fibroblasts• Scar formation• Connective tissue remodeling v3-CSBRP-May-2012
  52. 52. AngiogenesisDuring embryonic development:Vasculogenesis:• Angioblasts• HemangioblastsIn adults:Angiogenesis or Neovascularization• Endothelium of adjacent pre-existing vessels• BM endothelial progenitor cells (EPCs) v3-CSBRP-May-2012
  53. 53. AngiogenesisAngiogenesis from Preexisting Vessels:• Vasodilation• Degradation of the BM• Migration of endothelial cells• Proliferation of endothelial cells• Maturation of endothelial cells• Recruitment of periendothelial cells v3-CSBRP-May-2012
  54. 54. AngiogenesisAngiogenesis from Endothelial Precursor Cells (EPCs):• EPCs can be recruited from the bone marrow• The number of circulating EPCs increases greatly in patients with ischemic conditions• Examples: – Re-endothelization of vascular implants – Neovascularization of ischemic organs – Neovascularization of cutaneous wounds – Neovascularization of tumors v3-CSBRP-May-2012
  55. 55. AngiogenesisGrowth Factors and Receptors Involved in AngiogenesisVEGF is the most important growth factor in adult tissuesNewly formed vessels are fragile and need to become “stabilized” – Pericytes – Smooth muscle cellsFactors that participate in the stabilization process: – Angiopoietins 1 and 2 – PDGF, and – TGF-β v3-CSBRP-May-2012
  56. 56. ENDv3-CSBRP-May-2012
  57. 57. v3-CSBRP-May-2012