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Wound healing

Repair Responses After Injury And Inflammation

A Regeneration And Repair
  1. Wound healing
    1. Regeneration and repair of damaged cells and tissues starts as soon as the inflammatory process begins
    2. Wound healing involves separate processes
      1. Regeneration of the damaged tissue by cells of the same type
      2. Tissue repair with replacement by connective tissue
  2. Regeneration
    1. Different tissues have different regenerative capacities
    2. Labile cells
      1. Regenerate throughout life
      2. Examples: surface epithelial cells (skin and mucosal lining cells), hematopoietic & stem cells etc.
      3. Regenerate throughout life
      4. Examples: surface epithelial cells (skin and mucosal lining cells), hematopoietic & stem cells etc.
      5. Skin, oral cavity
      6. Cervix, vagina.
      7. Lining mucosa of all excretory ducts of the glands of body
      8. Columnar epithelium of GIT
      9. Uterus and fallopian tubes
      10. Transitional epithelium of urinary tract
      11. Cells of spleen, lymphoid and hematopoietic tissue. (RBCs and WBCs)
  3. Stable cells
    1. Replicate at a low level throughout life
    2. Have the capacity to divide if stimulated by some initiating event. They are in Go phase and can be stimulated to enter G1 phase            
    3. Examples: hepatocytes, proximal tubule cells, endothelium etc.
    4. Stable cells are present in-parenchymal cells of liver, kidney and pancreas, osteoblast, chondroblast smooth muscle cells.
    5. Permanent cells-skeletal and cardiac muscle cell and nerve cells.
    6. Myofibroblast is large fibroblast in granulation tissue which acquires features of smooth muscle cells.
    7. Fibroblast in repair stage is called 'juicy cells'.
  4. Permanent cells
    1. Cannot replicate - Example: neurons, cardiac muscle and skeletal muscle
  1. Tissue repair
    1. Replacement of a damaged area by a connective tissue scar
    2. Tissue repair is mediated by various growth factors and cytokines Q
      1. Transforming growth factor (TGF ß)
      2. Platelet derived growth factor (PDGF)
      3. Fibroblast growth factor (FGF)
      4. Vascular endothelial growth factor (VEGF)
      5. Epidermal growth factor (EDF)
      6. Tumor necrosis factor (TNF-?) and IL-l
    3. Granulation tissue is formed
      1. Synthetically active fibroblasts that lay collagen
      2. Capillary proliferation
      3. Chronic inflammatory cells - macrophage, lymphocytes.
    4. Wound contraction is mediated by myofibroblasts
    5. Scar formation

Description Of Healing Wounds

  1. Healing of a clear, uninfected surgical incision approximated by surgical sutures is k/a
    Primary UnionQ= Healing by first intention. Involves following changes:
    1. O hours -        
      1. Incision filled with clot (fibrin + blood cells)
    2. Within 24 hrs
      1. Neutrophils from margins infiltrate the clot
      2. Mitosis begins in epithelial basal cells
    3. 24 to 48 hrs -              
      1. Below scab continuous, but thin epith layer is formed
    4. Day 3 -                       
      1. Neutrophils are replaced by macrophages
      2. Granulation tissue begins to appear
      3. Epithelial cell proliferation continues
    5. Day 5-                        
      1. Incision space is filled with granulation tissue
      2. Neovascularization is maximum
      3. Collagen fibrils more abundant and bridge the incision
      4. Epidermis recovers normal thickness with surface keratinization
    6. WK2 -                        
      1. Accumulation of collagen + proliferation of fibroblasts
      2. (↓ Leukocyte, ↓ edema; regression of vascular channels)
    7. End of 1st month or 2nd month
      1. Scar comprises of cellular connective tissue without inflammatory
      2. infiltrate covered by intact epidermis
    8. Tensile Strength – Q
      May take months to yrs to become - maximum
      1. Sutures wounds - 70% after surgery
      2. 1st wk-Sutures removed – 10%  ↑s over next 4 wks
      3. 3rd month - Plateau 70-80% of unwounded skin (through life)
      4. Collagen - adult skin - type 1; early Granulation tissue type III, I
      5. Healing by Secondary intention: Q Occurs when there is more extensive loss of tissue as in infarction, inflammatory ulceration, abscess + large wounds.
  1. Common
  • Large tissue defect
  • Inflammatory reaction more intense.
  • Large amount of granulation tissue formed
  • Large scar
  • Wound contraction –
  • Most imp difference b/w 1° and 2° intention. Brought about by myofibroblast.
  1. Remodelling: Balance between collagen deposition and collagenase secretion.
    Degradation by Zinc metalloproteinase (of collagenase) -Q important for tissue remodeling, angiogenesis & cancer metastasis. Q
  • Collagenase produced by - fibroblasts, macrophages, neutrophils, synovial cell & some epithelia cell
  • Activated collagenase inhibited by tissue inhibitor of metalloproteinase.
  1. Factors affecting wound healing
  2. Local Factors
  • Blood supply              
  • Denervation                       
  • Local infection      
  • Foreign body
  • Hematoma                  
  • Mechanical stress  
  • Necrotic tissue           
  • Protection (dressings)
  • Surgical techniques           
  • Type of tissue
v. Systemic Factors
  • Age                            
  • Anemia                                   
  • Drugs (steroids, cytotoxic)                
  • Medications, intensive           
  • Antibiotic therapy                  
  • Genetic disorders                               
  • osteogenesis imperfecta         
  • Ehlers-Danlos syndromes,     
  • Marfan syndrome                                        
  • Hormones                   
  • Diabetes                                 
  • Malignant disease
  • Malnutrition               
  • Obesity                                   
  • Systemic infection
  • Temperature               
  • Trauma, hypovolemia             
  • Hypoxia
  • Uremia                                   
  • Vitamin deficiency (Vitamin C)
  • Trace metal deficiency (zinc, copper)
  1. Aberrations in wound healing
    1. Delayed wound healing
      1. Wound healing may be prolonged by foreign bodies, infection, ischemia, diabetes, malnutrition, or scurvy
    2. Hypertrophic scar
      1. Results in a prominent scar that is localized to the wound
      2. Excess production of collagen
    3. Keloid
      1. Genetic predisposition
      2. More common in African Americans
      3. Tends to affect the earlobes, face, neck, sternum, and forearms.
      4. May produce large tumor like scars, which often extend beyond the injury site.
      5. Excess production of collagen that is predominantly type III.
    4. Exuberant granulation tissue (proud flesh) - Increased granulation tissue that blocksre epithelization of wound
    5. Desmoid / fibromatosis - Exuberant proliferation of fibroblasts and other connective tissue components Q
  2. Connective tissue components
    1. Collages (over 14 types)
      1. Type I
        1. Most common         
        2. High tensile strength          
        3. Skin, bone, tendons and 'most organs
      2. Type II: cartilage and vitreous humor
      3. Type III: Granulation tissue, embryonic tissue, uterus, keloids
      4. Type IV: basement 'membranes
      5. Hydroxylation of collagen is mediated by vitamin C
      6. Cross -linking of collagen is performed by lysyl oxidase. Copper is a required cofactor
    2. Other extracellular matrix components
      1. Elastic fibres
        1. Elastin proteins are aligned on a fibrillin framework
        2. Defects in fibrillin are found in Marfan syndrome
      2. Adhesion molecules
        1. Fibronectin             
        2. Laminin
      3. Proteoglycans and glycosaminoglycans
        1. Heparan sulfate     
        2. Chondroitin sulfate
    3. Basement membranes
      1. The basement membrane has a net negative charge Composition of basement membranes
        1. Collagen type IV                
        2. Proteoglycans (heparan sulfate)     
        3. Laminin
Table: Growth Factors and cytokines involved in Regeneration and wound healing.
Cytokine Symbol Source Functions
Epidermal growth factor EGF Activated macrophages, salivary glands, keratinocytes, and many other cells Mitogenic for keratinocytes and fibroblasts; stimulates keratinocyte migration and granulation tissue formation
Transforming growth factor α TGF-α Activated macrophages, T lymphocytes, keratinocytes, and many other cells Similar to EGF; stimulates replication of hepatocytes and many epithelial cells
Hepatocyte growth factor (scatter factor) HGF Mesenchymal cells Enhances proliferation of epithelial and endothelial cells, and of hepatocytes; increases cell motility
Vascular endothelial cell growth factor (isoforms A, B, C, D) VEGF Mesenchymal cells Increases vascular permeability; mitogenic for endothelial cells (see text)
Platelet-derived growth factor (isoforms A, B, C, D) PDGF Platelets, macrophages, endothelial cells, keratinocytes, smooth muscle cells Chemotactic for PMNs, macrophages, fibroblasts, and smooth muscle cells; activates PMNs, macrophages, and fibroblasts; mitogenic for fibroblasts, endothelial cells, and smooth muscles cells; stimulates production of MMPs, fibronectin, and HA; stimulates angiogenesis and wound remodeling; regulates integrin expression
Fibroblast growth factor 1 (acidic), -2 (basic), and family FGF-1, -2 Macrophages, mast cells, T lymphocytes, endothelial cells, fibroblasts, and many tissues Chemotactic for fibroblasts; mitogenic for fibroblasts and keratinocytes; stimulates keratinocyte migration, angiogenesis, wound contraction, and matrix deposition
Transforming growth factor β(isoforms 1, 2, 3) TGF-β Platelets, T lymphocytes, macrophages, endothelial cells, keratinocytes, smooth muscle cells, fibroblasts Chemotactic for PMNs, macrophages, lymphocytes, fibroblasts, and smooth muscle cells; stimulates TIMP synthesis, angiogenesis, and fibroplasia; inhibits production of MMPs and keratinocyte proliferation; regulates integrin expression and other cytokines
Keratinocyte growth factor (FGF-7) KGF Fibroblasts Stimulates keratinocyte migration, proliferation, and differentiation

Tissue Repair: Cell Growth, Fibrosis & Wound Healing

Repair Regeneration → required Basement membrane
By connective tissue (fibroplasias/ fibrosis) => scar formation occurs
Size of population: determined by cell proliferation differentiation,and Death → CONTROL OF

Stimuli of Proliferation: depends upon
  1. Injury                       
  2. Cell death               
  3. Mechanical deformation

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