PHRD5015 Lecture 14 - Wound Healing

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PHRD5015 Lecture 14 - Wound Healing
2013-10-29 22:05:40
PHRD5015 Wound Healing

Wound Healing
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  1. occurs after inflammatory even associated with tissue injury
  2. replacement of original tissue with scar tissue
  3. scar tissue
    • consists primarily of collagen
    • restores tensile strength of the tissue
  4. duration of wound cleanup
    • initiated before healing commences
    • continues as healing proceeds
  5. cleanup
    • macrophages phagocytose debris (microorganisms, RBCs, debris from necrotic cells) at the site of injury before healing begins
    • remaining debris drained away via lymphatics
  6. 3 major tissue healing processes
    • 1) filling in
    • 2) sealing the wound
    • 3) shrinking the wound
  7. healing process by which wounds heal under conditions of minimal tissue loss
    primary intention
  8. healing process by which a wound with a large open area such as a pressure sore or a burn wiht significant tissue loss must generate many new cells to close
    • secondary intention
    • takes much longer
  9. phase of healing that begins 3-4 days after the injury and continues for up to 2 weeks
    reconstructive phase
  10. events during reconstructive phase
    • fibroblasts proliferate, serve as connective tissue, & secrete collagen
    • epithelialization occurs
    • wound contracts
    • cells begin differentiation
  11. phase of healing that begins several weeks after injury and may proceed for up to 2 years
    maturation phase
  12. events during the maturation phase
    • cells continue to differentiate
    • scar forms & may be remodeled
  13. how a surgical wound is initially sealed off
    by a blood clot containing fibrin, the platelet plug, and trapped dead cells within hours after closure
  14. during initial steps of reconstruction, serves as a scaffold used to regenerate cells or by collagen to fill the wound volume
    fibrin mesh
  15. primary system limiting the size of the blood clot
    • fibrinolytic system 
    • aka plasminogen-plasmin system
  16. serine protease that degrades fibrin polymers
  17. precursor of plasmin, made in the liver
  18. 2 ways plasminogen cleavage is regulated
    • 1) t-PA
    • 2) u-PA
  19. t-PA
    • tissue plasminogen activator
    • secreted on the tissue side of endothelial cells
    • activated by fibrin binding & can cleave plasminogen
  20. u-PA
    • urokinase-like plasminogen activator
    • works in blood
    • u-PA receptor expressed by VECs at the site of injury
  21. PAI
    • plasminogen activator inhibitor
    • inhibits t-PA and u-PA
  22. 2-AP
    • alpha 2 antiplasmin
    • directly inhibits plasmin
  23. new tissue (derived from connective tissue cells) that begins growing inward to fill the wound area
    granulation tissue
  24. type of connective tissue cell primarily concerned with secreting collagen
  25. during wound healing, these cells are activated and proceed to proliferate, differentiate, and migrate to the wound area
  26. how angiogenesis is stimulated
    via the HIF-1 signal when there is a need for additional nutrients in an area
  27. what gives granulation tissue its granular character
    presence of capillaries
  28. 3 molecules secreted by macrophages during the reconstructive phase
    • 1) TGF 
    • 2) VEGF
    • 3) MMPs
  29. role of TGF during the reconstruction phase
    stimulates fibroblasts in the area to secrete procollagen
  30. role of angiogenesis factors (VEGF) during the reconstructive phase
    promotes creation of tip and stalk cells and their migration towards the VEGF source
  31. role of MMPs during the reconstructive phase
    • degrade ECM
    • help with angiogenesis
    • some remodeling of the wound
    • (matrix metalloproteinases)
  32. macrophage change during the reconstructive phase
    differentiation from M1 to M2 by IL-4 & IL-13 signaling
  33. M1
    soldier macrophages
  34. M2
    healer macrophages
  35. process in which epithelial cells grow into the wound area to help seal it as the clot is being dissolved and granulation tissue is being formed
  36. epithelial cells use these as guides during epithelialization
    collagen fibers
  37. most important component during the reconstruction phase
    fibroblasts -> collagen source
  38. how long it takes from the time they enter the wound for fibroblasts to secrete collagen
    ~6 days
  39. what the fibroblast differentiates into when it enters the wound
  40. structure of initially-secreted collagen
    3 polypeptide chains that are cross-linked
  41. duration of the process of creating the final collagen matrix
  42. final step of reconstruction
    wound contraction
  43. myofibroblasts
    • contains properties of muscle cells & fibroblasts
    • look like fibroblasts but contain actin-myosin fibers to allow contraction
    • form layer along wound bed
  44. phase that begins 2 weeks after the wounding event and last for years
    maturation phase
  45. processes that continue during the maturation phase
    • 1) collagen matrix assembly
    • 2) tissue regeneration
    • 3) wound contraction
  46. during this phase, scar tissue is remodeled and capillaries disappear
    maturation phase
  47. 4 reasons hemorrhage slows healing
    • 1) phagocytosis of more cells takes longer
    • 2) larger clot = O2 diffusion barrier
    • 3) fibrous adhesions from additional fibrin of the clot
    • 4) bacteria use blood as food source -> continue infection
  48. decreased blood volume
  49. cause of hypovolemia that slows the inflammatory process
    • malnutrition
    • dehydration
    • hemorrhage
  50. response of blood vessels to hypovolemia
    • contraction
    • makes it more difficult for inflammatory cells to reach target
  51. reasons glucocorticoids slow wound healing
    • inhibition of:  
    • fibroblast migration
    • fibroblast collagen deposition
    • epithelial migration
    • angiogenesis
    • wound contraction
  52. disease caused by ascorbic acid deficiency that affects collagen matrix assembly
  53. collagen overproduction caused by an imbalance between collagen synthesis & degradation rates resulting in a large scar formation
  54. cause of most dysfunctions in collage assembly
    nutritional deficiencies
  55. causes of macrophage dysregulation
    continued reinjury & reinfection
  56. kinds of cells that can become myofibroblasts
    • fibroblasts
    • epithelial cells
    • endothelial cells
    • pericytes
    • smooth muscle cells
  57. ED-A
    • alternatively spliced domain in fibronectin that, when expressed, potentiates TGF signaling
    • -> disruption decreases myofibroblast formation
  58. relationship between myofibroblasts and macrophages
    • reciprocal activation
    • myofibroblasts secrete activating cytokines, macrophages secrete TGF, PDGF, & ED-A containing fibronectin
  59. how precursor cells are directed towards myofibroblast differentiation
    exposure to TGF and ED-A domain of fibronectin
  60. 4 therapeutic strategies for fibrosis
    • 1) recombinant ED-A
    • 2) ED-A fibronectin Ab's
    • 3) TGF inhibitors
    • 4) pro-fibrotic cytokine inhibitors
  61. what potentiates the TGF signal
    interaction with ED-A domain of fibronectin
  62. how myofibroblasts interact with collagen fibers
    via integrins
  63. dietary necessity for MMP production
  64. impairing effect of dressing in the would healing process
    dressings can absorb migrating epithelial cells and excess fluid, removing them from the site of healing
  65. imparing effect of would cleaning in the healing process
    iodine & hydrogen peroxide solutions kill pathogens AND epithelial cells that cover the wound area
  66. deformity due to excessive wound contraction caused by excessive myofibroblast activity
  67. problems associated with burn victims
    • high probability of infection
    • likelihood of developing ARDS
    • organ failure
  68. important aspect of wound healing in burn victims
    • nutrition
    • huge nutritional requirement as tissue proliferation is occurring at multiple sites
  69. drug shown to be helpful in improving healing time in burn victims
    • beta blockers (ex: propranolol)
    • -> decrease energy consumption throughout the body, allowing more nutrition to be used by cells for healing