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

Abstract

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 elasticity 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.

Role of corticosteroids in skin physiology and therapeutic potential of an 11β‐HSD1 inhibitor: A review

“…They also hypothesized that pharmacological manipulation of 11β‐HSD1 expression would improve aspects of residual scarring. By measuring skin 11β‐HSD1 expression in both mice and humans and using 11β‐HSD1 knockout mice to further explore the effects of 11β‐HSD1 activity on wound healing from burn trauma and quality of scar formation, Tsai et al 33 . demonstrated 11β‐HSD1 expression levels increased significantly in both mice and human skin after burn trauma ( P < 0.05).…”

“…They cited several previous studies that reported both positive and negative findings regarding the ability of human skin to synthesize cortisol de novo, emphasizing the need to treat results from studies involving mice with caution. Furthermore, Tsai et al 33 . noted that a limitation in using a mouse model examining skin 11β‐HSD1 expression in wound healing from burn trauma is that there are differences in aspects of wound healing between mice and humans.…”

“…Tsai et al 33 explored the role of 11b-HSD1 in wound healing from burn trauma. They hypothesized burn trauma would activate 11b-HSD1 expression and local cortisol synthesis, with important effects on wound healing, scarring, and fibrosis.…”

“…By measuring skin 11b-HSD1 expression in both mice and humans and using 11b-HSD1 knockout mice to further explore the effects of 11b-HSD1 activity on wound healing from burn trauma and quality of scar formation, Tsai et al 33 demonstrated 11b-HSD1 expression levels increased significantly in both mice and human skin after burn trauma (P < 0.05). They also demonstrated that application of a slow-releasing inactive glucocorticoid, which is then activated by local 11b-HSD1 in the skin, reduces the initial wound healing rate but significantly improves scarring characteristics.…”

Cis-2-Decenoic Acid and Bupivacaine Delivered from Electrospun Chitosan Membranes Increase Cytokine Production in Dermal and Inflammatory Cell Lines

“…Either behavior can benefit burn wound healing depending on the severity of the injury. An over production of collagen results in disorganized scar tissue, yet collagen production is necessary for tensile strength, vascularization, and remodeling of regenerated tissue [32,33]. While collagen production in response to C2DA has not been tested previously, studies of other fatty acids have shown a concentration-dependent relationship between treatment and collagen stimulation, in that high concentrations of fatty acids can inhibit collagen deposition [34,35].…”