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occurs after inflammatory even associated with tissue injury
healing
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replacement of original tissue with scar tissue
repair
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scar tissue
- consists primarily of collagen
- restores tensile strength of the tissue
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duration of wound cleanup
- initiated before healing commences
- continues as healing proceeds
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cleanup
- macrophages phagocytose debris (microorganisms, RBCs, debris from necrotic cells) at the site of injury before healing begins
- remaining debris drained away via lymphatics
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3 major tissue healing processes
- 1) filling in
- 2) sealing the wound
- 3) shrinking the wound
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healing process by which wounds heal under conditions of minimal tissue loss
primary intention
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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
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phase of healing that begins 3-4 days after the injury and continues for up to 2 weeks
reconstructive phase
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events during reconstructive phase
- fibroblasts proliferate, serve as connective tissue, & secrete collagen
- epithelialization occurs
- wound contracts
- cells begin differentiation
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phase of healing that begins several weeks after injury and may proceed for up to 2 years
maturation phase
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events during the maturation phase
- cells continue to differentiate
- scar forms & may be remodeled
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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
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during initial steps of reconstruction, serves as a scaffold used to regenerate cells or by collagen to fill the wound volume
fibrin mesh
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primary system limiting the size of the blood clot
- fibrinolytic system
- aka plasminogen-plasmin system
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serine protease that degrades fibrin polymers
plasmin
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precursor of plasmin, made in the liver
plasminogen
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2 ways plasminogen cleavage is regulated
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t-PA
- tissue plasminogen activator
- secreted on the tissue side of endothelial cells
- activated by fibrin binding & can cleave plasminogen
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u-PA
- urokinase-like plasminogen activator
- works in blood
- u-PA receptor expressed by VECs at the site of injury
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PAI
- plasminogen activator inhibitor
- inhibits t-PA and u-PA
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 2-AP
- alpha 2 antiplasmin
- directly inhibits plasmin
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new tissue (derived from connective tissue cells) that begins growing inward to fill the wound area
granulation tissue
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type of connective tissue cell primarily concerned with secreting collagen
fibroblasts
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during wound healing, these cells are activated and proceed to proliferate, differentiate, and migrate to the wound area
fibrocytes
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how angiogenesis is stimulated
via the HIF-1 signal when there is a need for additional nutrients in an area
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what gives granulation tissue its granular character
presence of capillaries
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3 molecules secreted by macrophages during the reconstructive phase
- 1) TGF
 - 2) VEGF
- 3) MMPs
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role of TGF during the reconstruction phase
stimulates fibroblasts in the area to secrete procollagen
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role of angiogenesis factors (VEGF) during the reconstructive phase
promotes creation of tip and stalk cells and their migration towards the VEGF source
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role of MMPs during the reconstructive phase
- degrade ECM
- help with angiogenesis
- some remodeling of the wound
- (matrix metalloproteinases)
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macrophage change during the reconstructive phase
differentiation from M1 to M2 by IL-4 & IL-13 signaling
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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
epithelialization
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epithelial cells use these as guides during epithelialization
collagen fibers
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most important component during the reconstruction phase
fibroblasts -> collagen source
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how long it takes from the time they enter the wound for fibroblasts to secrete collagen
~6 days
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what the fibroblast differentiates into when it enters the wound
myofibroblast
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structure of initially-secreted collagen
3 polypeptide chains that are cross-linked
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duration of the process of creating the final collagen matrix
months
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final step of reconstruction
wound contraction
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myofibroblasts
- contains properties of muscle cells & fibroblasts
- look like fibroblasts but contain actin-myosin fibers to allow contraction
- form layer along wound bed
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phase that begins 2 weeks after the wounding event and last for years
maturation phase
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processes that continue during the maturation phase
- 1) collagen matrix assembly
- 2) tissue regeneration
- 3) wound contraction
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during this phase, scar tissue is remodeled and capillaries disappear
maturation phase
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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
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decreased blood volume
hypovolemia
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cause of hypovolemia that slows the inflammatory process
- malnutrition
- dehydration
- hemorrhage
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response of blood vessels to hypovolemia
- contraction
- makes it more difficult for inflammatory cells to reach target
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reasons glucocorticoids slow wound healing
- inhibition of:
- fibroblast migration
- fibroblast collagen deposition
- epithelial migration
- angiogenesis
- wound contraction
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disease caused by ascorbic acid deficiency that affects collagen matrix assembly
scurvy
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collagen overproduction caused by an imbalance between collagen synthesis & degradation rates resulting in a large scar formation
keloid
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cause of most dysfunctions in collage assembly
nutritional deficiencies
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causes of macrophage dysregulation
continued reinjury & reinfection
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kinds of cells that can become myofibroblasts
- fibroblasts
- epithelial cells
- endothelial cells
- pericytes
- smooth muscle cells
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ED-A
- alternatively spliced domain in fibronectin that, when expressed, potentiates TGF signaling
- -> disruption decreases myofibroblast formation
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relationship between myofibroblasts and macrophages
- reciprocal activation
- myofibroblasts secrete activating cytokines, macrophages secrete TGF, PDGF, & ED-A containing fibronectin
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how precursor cells are directed towards myofibroblast differentiation
exposure to TGF and ED-A domain of fibronectin
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4 therapeutic strategies for fibrosis
- 1) recombinant ED-A
- 2) ED-A fibronectin Ab's
- 3) TGF inhibitors
- 4) pro-fibrotic cytokine inhibitors
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what potentiates the TGF signal
interaction with ED-A domain of fibronectin
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how myofibroblasts interact with collagen fibers
via integrins
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dietary necessity for MMP production
zinc
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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
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imparing effect of would cleaning in the healing process
iodine & hydrogen peroxide solutions kill pathogens AND epithelial cells that cover the wound area
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deformity due to excessive wound contraction caused by excessive myofibroblast activity
contracture
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problems associated with burn victims
- high probability of infection
- likelihood of developing ARDS
- organ failure
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important aspect of wound healing in burn victims
- nutrition
- huge nutritional requirement as tissue proliferation is occurring at multiple sites
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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
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