pathogenesis

Last reviewed 01/2018

Keloid scars are a result of an imbalance in wound healing physiology with an excessive deposition of collagenous connective tissue. There is excessive production of collagen, reduced degradation or both processes occurring concurrently. A variety of theories have been put forward to explain this:

• excessive inflammation:
  • fibroproliferative scars have many features of ongoing inflammation
  • mammalian wounds in utero have a blunted inflammatory response and less tendency to scarring
  • addition of anti-TGF beta-1 or 2 to wounds (profibrogenic, inflammatory molecules) reduces scarring in adult rodent wounds, the same is true for the addition of exogenous TGF beta-3 (antifibrogenic)
  • other suggested pro-fibrogenic, inflammatory molecules suggested to be increased in keloid wounds include FGF, EGF, PDGF, IGF-1 and IL-4
  • anti-fibrogenic molecules include TNF-alpha, interferon gamma, and IL-1
  • the balance of these molecules is suggested to attract an excessive number of fibroblasts which secrete increased amounts of collagen
• fibroblast abnormality:
  • cultured fibroblasts from keloids demonstrate increased procollagen production with elevated levels of type I to type III collagen
  • keloid, as opposed to normal, fibroblasts:
    • secrete other extracellular matrix elements at increased concentration including fibronectin, elastin and proteoglycans
    • secrete such molecules at an increased rate in response to cues such as increased tension across a collagenous scaffold in which they are seeded and the application of cytokines
  • there may be an intrinsic failure of myofibroblasts to undergo a normal wave of apoptosis at the end of the proliferative phase of wound healing
• aberrant remodelling:
  • reduced activity of the enzymes which remodel collagen in the late stages of scar production
  • alpha-1-antitrypsin and alpha-2-macroglobulin are raised at this time and both are inhibitors of collagenases
  • TIMP molecules may have a similar action
• microvascular hypoxia:
  • electron micrographic studies suggest that although there are increased numbers of vessels in the keloid scar, they may be occluded due to endothelial cell division
  • the subsequent hypoxia is thought to be a stimulus to fibroblast growth
• immune dysregulation:
  • both humoral and cell-mediated immunity seem to be aberrant in keloidal scarring
  • increased levels of histamine and immunoglobulins have been identified
  • a specific anti-nuclear antibody to keloidal cells has been noted; this may act as a stimulant
  • antigen-presenting cells may downregulate the T cell response to injury by reducing levels of the antifibrogenic cytokine IL-1
• miscellaneous theories:
  • excessive responsiveness to hormonal fluxes
  • excess neuronal re-innervation
  • increased levels of wound nitric oxide or free radicals
  • altered lipid environment of the wound
  • reduced barrier function of the epidermis