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