Skin 11β-hydroxysteroid dehydrogenase type 1 enzyme expression regulates burn wound healing and can be targeted to modify scar characteristics

Background:Excessive scarring and fibrosis are the most severe and common complications of burn injury.Prolonged exposure to high levels of glucocorticoids detrimentally impacts on skin,leading to skin thinning and impaired wound healing.Skin can generate active glucocorticoids locally through expression and activity of the 11β-hydroxysteroid dehydrogenase type 1 enzyme(11β-HSD1).We hypothesised that burn injury would induce 11β-HSD1 expression and local glucocorticoid metabolism,which would have important impacts on wound healing,fibrosis and scarring.We additionally proposed that pharmacological manipulation of this system could improve aspects of post-burn scarring.Methods:Skin 11β-HSD1 expression in burns patients and mice was examined.The impacts of 11β-HSD1 mediating glucocorticoid metabolism on burn wound healing,scar formation and scar elas-ticity and quality were additionally examined using a murine 11β-HSD1 genetic knockout model.Slow-release scaffolds containing therapeutic agents,including active and inactive glucocorticoids,were developed and pre-clinically tested in mice with burn injury.Results:We demonstrate that 11β-HSD1 expression levels increased substantially in both human and mouse skin after burn injury.11β-HSD1 knockout mice experienced faster wound healing than wild type mice but the healed wounds manifested significantly more collagen deposition,tensile strength and stiffness,features characteristic of excessive scarring.Application of slow-release prednisone,an inactive glucocorticoid,slowed the initial rate of wound closure but significantly reduced post-burn scarring via reductions in inflammation,myofibroblast generation,collagen production and scar stiffness.Conclusions:Skin 11β-HSD1 expression is a key regulator of wound healing and scarring after burn injury.Application of an inactive glucocorticoid capable of activation by local 11β-HSD1 in skin slows the initial rate of wound closure but significantlyimproves scar characteristics post burn injury.

The contradictory role of androgens in cutaneous and major burn wound healing

Wound healing is a complex process involving four overlapping phases:haemostasis,inflammation,cell recruitment and matrix remodeling.In mouse models,surgical,pharmacological and genetic approaches targeting androgen actions in skin have shown that androgens increase interleukin-6 and tumor necrosis factor-αproduction and reduce wound re-epithelization and matrix deposition,retarding cutaneous wound healing.Similarly,clinical studies have shown that cutaneous wound healing is slower in men compared to women.However,in major burn injury,which triggers not only local wound-healing processes but also systemic hypermetabolism,the role of androgens is poorly understood.Recent studies have claimed that a synthetic androgen,oxandrolone,increases protein synthesis,improves lean body mass and shortens length of hospital stay.However,the possible mechanisms by which oxandrolone regulates major burn injury have not been reported.In this review,we summarize the current findings on the roles of androgens in cutaneous and major burn wound healing,as well as androgens as a potential therapeutic treatment option for patients with major burn injuries.