Path Tissue Repair & Regeneration (5)

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  1. In response to cell injury, a tissue can either:
    be regenerated or repaired
  2. Regeneration
    • replacement of damaged components & return to normal state
    • Renewing Tissues: a complete regeneration (can occur in the epidermis, GI tract epithelium, or hematopoietic system)
    • Stable Tissue: compensatory growth (like in the liver or kidney)
  3. Components of Tissue Regeneration and Repair
    • Parenchymal cells
    • Stromal cells
    • Extracellular Matrix
    • Growth Factors
  4. What are 3 groups of cells according to their regenerative capacity?
    • 1. labile
    • 2. stable
    • 3. permanent
    • regeneration of an injured tissue or organ depends on its cellular composition
  5. Labile Cells
    • continuously dividing
    • proliferate continuously, replacing cells that are destroyed as part of a turnover process
    • eg. epithelia (skin, respiratory, urinary, gastro- intestinal, genital mucosa) or hemopoietic cells
  6. Stable Cells
    • quiescent
    • normally exhibit slow turnover, however they may replicate rapidly in response to growth factors & completely regenerate tissues of origin
    • eg. glandular organs (liver, kidney, pancreas, endocrine glands), mesenchymal tissues (bone, cartilage, vessels), or glia
  7. Permanent Cells
    • non-dividing
    • CANNOT undergo division, or have limited mitotic activity in post-natal life
    • eg. skeletal & cardiac muscle, smooth Muscle (which can actually have very limited regenerative capacity), or neurons
  8. Stem Cells
    • less differentiated precursor or pluripotential cells
    • cell regeneration often depends on the existence of less differentiated precursor cells like pluripotential stem cells
  9. 3 signaling pathways growth factors can activate
    • 1. Tyrosine Kinase Activity
    • 2. No Intrinsic Enzyme Activity (JAK/STAT)
    • 3. G-protein coupled receptors
  10. Receptors w/ Tyrosine Kinase Activity
    • activation triggers a cascade of phosphorylating events through
    • 1. MAP kinases (mitogen-activated protein)
    • 2. PI-3 kinases (phosphatidylinositol-3)
    • result is always transcription factor activation → DNA replication
  11. Which growth factors bind to receptors that have tyrosine kinase activity?
    • EGF     Epidermal Growth Factor
    • TGF-α  Transforming GF-α
    • VEGF   Vascular Endothelial GF
    • PDGF   Platelet-derived GF
    • FGF     Fibroblast GF
    • HGF    Hepatocyte GF
  12. Receptors Without Intrinsic Enzyme Activity
    • their activation leads to an association w/ intracellular protein kinases called Janus kinases (JAKs)
    • JAKs activate STATs, cytoplasmic transcription factors that transduce signals & move into the nucleus to activate gene transcription
  13. Which growth factors bind to receptors that activate transcription via the JAK/STAT pathway?
    • Cytokines
    • Interferons
    • Colony-stimulating Factors
    • Growth Hormones
    • Erythropoietin
  14. G-protein-coupled Receptors
    • 7-transmembrane G-protein-coupled receptor activation triggers the cAMP pathway w/ multiple effects
    • can also activate the 1,4,5-triphosphate (IP3) pathway, which releases calcium from ER
  15. Which growth factors bind to G-protein coupled receptors?
    • Epinephrine
    • Vasopressin
    • Serotonin
    • Histamine
    • Glucagon
    • Chemokines ("che" rhymes w/ "G")
  16. Roles of Extracellular Matrix
    • 1. mechanical support: for cell anchorage & cell migration
    • 2. control of cell growth: by signaling through cellular receptors of the integrin family
    • 3. scaffolding for tissue renewal: basement membrane or stromal scaffold is critical for normal structure & regeneration if needed
    • 4. establishment of tissue microenvironment: basement membrane serves as a boundary & filter
    • 5. storage & presentation of regulatory molecules: GFs are excreted & stored in the ECM of some tissues
    • 6. intact ECM is required for tissue REGENERATION: if ECM is damaged regeneration can't occur, only scar formation
    • Image Upload
  17. What must be structurally intact for regeneration to be successful?
    • residual connective tissue
    • the integrity of the stroma is important, otherwise regeneration is incomplete & scarring occurs
  18. Interstitial Matrix
    • found between cells in the connective tissue, epithelium, & supportive vascular & smooth muscle structures
    • made by mesenchymal cells
    • amorphous gel containing collagens, fibronectin, elastin, proteoglycans, hyaluronate etc.
  19. Basement Membrane
    • highly organized matrix containing amorphous nonfibrillar type IV collagen & laminin
    • made by overlying epithelium & underlying mesenchymal cells
    • associated w/ epithelial cells, endothelial cells, & muscle cells
  20. ECM Components
    • 1. Fibrous Structural Proteins (collagen, elastin)
    • 2. H2O-hydrated Gels (proteoglycans, hyaluronan; act as growth factor reservoirs)
    • 3. Adehsive Glycoproteins (fibronectin, laminin)
    • 4. Adhesion Receptors (CAMs, cellular adhesion molecules)
  21. Granulation Tissue
    • new connective tissue + tiny blood vessels that form on the surfaces of a wound during the healing process
    • surface of tissue LOOKS granular
    • forms within 3-5 days after injury
  22. Resolution Phase of Healing
    • pathogens, damaged tissue, & RBCs are removed by macrophages
    • failure to remove all of the damaged cells & pathogens may retrigger inflammation
    • he defines this as returning an organ to its original function without diminishing its capacity (no scarring) & gives the example uncomplicated Pneumonia
    • examples shows a Streptococcus pneumoniae infection in the lung that clears up
  23. Connective Tissues (Scar) Repair Steps
    • 1. Angiogenesis: formation of new BVs
    • 2. Fibroblast migration & proliferation
    • 3. ECM deposition
    • 4. Granulation tissue formation
    • 5. Remodeling: maturation & reorganization of the fibrous tissue
    • 6. Wound contraction + development of wound strength
  24. Angiogenesis
    • formation of new blood vessels from existing vessels
    • 1. Nitric Oxide → Vasodilation
    • 2. VEGF → Increased permeability,
    • 3. MMP → Basement membrane breaks down
    • 4. Plasminogen Activator → disrupts epithelial cell (EC) cell-cell contact
    • 5. ECs proliferate & migrate
    • 6. ECs mature & remodel into capillary tubes
    • 7. peri-endothelial cells (capillaries, pericytes, larger vessels, smooth muscle) are recruited
    • 8. basement membrane forms & cell migration & proliferation stops
  25. What are the most important growth factors involved in angiogenesis?
    • VEGF
    • FGF-2
    • Angiopoietins (Ang)
  26. Vascular Endothelial Cell Growth Factor (VEGF)
    stimulates angiogenesis, endothelial cell mitogen (sitmulates mitosis), & increases vascular permeability
  27. FGF-2 (Basic Fibroblast Growth Factor)
    • binds to membrane receptor w/ tyrosine kinase activity
    • enhances endothelial cell proliferation
    • enhances epithelial cell differentiation & motility + migration
    • promotes migration of macrophages & fibroblasts to areas of cell damaged
  28. Angiopoietins (Ang) 1 & 2
    • stabilize newly formed vessels
    • recruit pericytes (capillaries) & smooth muscle cells (large vessels)
    • enhances deposit of ECM (mediates vessel maturation from simple tubes into more elaborate vascular structures)
    • Ang 1 maintain EC quiescence
  29. EMC Deposition & Scar Formation
    • granulation tissue is laid down & then converted into a scar composed of fibroblasts & collagen
    • fibroblasts, stimulated by growth factors, migrate to & proliferate at repair sites
    • in this situation there's minimal cellular proliferation & significant deposition of fibrogenic ECM agents
    • stimulated by TGF-β/PDGF/FGF, & cytokines
    • scar formation lessens ECM degradation
  30. Matrix Metalloproteinases (MMPs)
    • enable cells to migrate through stroma by degrading matrix proteins at the site of injury; are the MAIN digestive enzymes in REMODELING
    • are involved in cell-cell communication & the activation or inactivation of bioactive molecules
    • they also influence cell growth & apoptosis
  31. How are matrix metalloproteinases (MMPs) inactivated?
    by binding to specific proteinase inhibitors (plasma-derived proteinase inhibitor, α-2-macroglobulin), plus a family of endogenous tissue inhibitors of metalloproteinases
  32. Healing by First Intention
    • occurs in response to a clean surgical incision w/ minimal cell death & minimal basement membrane disruption
    • such wounds have opposed edges
    • epithelial regeneration predominates over fibrosis
    • a small scar & MINIMAL wound contraction result
    • 0 hrs incision fills w/ clotted blood → 3-24 hrs neutrophils infiltrate the clot → 24-48 hrs epithelial cell migration & deposition of BM
  33. Healing by Second Intention
    • wounds have separated edges
    • more extensive tissue loss
    • larger clot or scab
    • more intense inflammation
    • more granulation tissue
    • larger scar
    • wound contraction (myofibroblasts)
  34. Wound Strength
    • initially depends on suturing
    • after sutures are removed, wound strength is
    • about 10% of what it was normally
    • it increases rapidly over the next 4 weeks, however tensile strength eventually plateaus (‘maxes out’) at 70-80% ~3 months
    • it usually does not improve beyond that point
    • (almost never returns to 100% ability)
  35. What are some local & systemic effects that Influence wound healing?
    • the size, location, & type of wound

    • local factors such as infection, mechanical forces, & foreign bodies

    • aberrations of cell growth & ECM production

    • systemic factors (nutritional, metabolic [diabetes slows wound healing], or circulation status & the presence of anti-inflammatory agents, which can impede the inflammatory-repair process)
  36. Complications in Cutaneous Wound Healing
    • 1. Deficient scar formation: inadequate granulation tissue or collagen deposition & remodeling, wound dehiscence (ruptures along suture line), or ulceration
    • 2. Excessive Repair: excessive granulation (proud flesh) can protrude above the skin & block re-epithelialization
    • 3. Keloid: excessive collagen accumulation forms a raised hypertrophic scar beyond the original area of injury w/out regression (no plastic surgery)
    • 4. Formation of contractures: excessive wound contraction can cause deformity or limit joint mobility (bad burns)
  37. Repair
    • restoration of tissue architecture & function after an injury
    • Wound: consists of would healing & scar formation (too much can affect organ function)
    • Chronic Inflammation: leads to fibrosis
  38. Scar Formation
    • with substantial tissue damage, the healing process is accompanied by the deposition of connective (fibrous) tissue (mainly collagen), leading to the formation of a scar
    • occurs when a tissue is incapable of complete restoration
  39. Fibrosis
    • significant scarring
    • extensive deposition of collagen (fibrous tissue) in tissues & organs
    • associated with chronic inflammatory diseases such as rheumatid arthritis & cirrhosis where there is persistence of an initial injury or the inflammatory response
    • ongoing inflammation drives progressive tissue injury & fibrosis
    • Image Upload
  40. What sustains the synthesis & secretion of growth factors, fibrogenic cytokines, & other biologically active molecules that promote fibrosis?
    lymphocyte-macrophage interactions
  41. Organization
    fibrosis/scarring that develops in a cavity or lumen occupied by an inflammatory exudate, clot, or thrombus
Card Set:
Path Tissue Repair & Regeneration (5)
2014-01-26 01:19:38
MBS Pathology
Exam 1
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