SUN-217 Skin Glucocorticoid Metabolism in Burn Injury: Towards Novel Treatments That Reduce Scarring

Abstract

The most common and severe complication of burn injury is the development of excessive scarring/tissue fibrosis. No current treatments reduce scarring after burns. Prolonged exposure to high levels of glucocorticoids (Cushing’s syndrome) detrimentally impacts skin, leading to reduced collagen production 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 local glucocorticoid activation by 11β-HSD1 is an important regulator of wound healing, fibrosis and scarring after burn injury. We additionally proposed that pharmacological manipulation of this system would improve outcomes of burn wound healing.We examined glucocorticoid metabolism (by RT-PCR, immunohistochemistry and specific enzyme activity assays) in burn and non-burn skin from burn injury patients (n=14) and mouse models of burn injury (1cm2 full thickness burn in C57Bl/6 mice). We utilised mice with genetic or pharmacological deletion of 11β-HSD1 in skin to evaluate the effects of 11β-HSD1 on burn injury healing, wound fibrosis and skin properties (by atomic force microscopy and tensile property testing) after wound healing. We also developed slow release scaffolds containing therapeutic agents including inactive glucocorticoids (prednisone) that are selectively reactivated in skin cells expressing 11β-HSD1.The expression of 11β-HSD1 in human and mouse skin increased substantially after burn injury (7.1+/-1.8 fold increase on day 4–9 post burn compared to non-burn skin, p<0.05). Early after injury, expression was primarily in immune cells but at later stages in fibroblasts. Mice with 11β-HSD1 deletion experienced faster wound healing post burn (17% reduced wound area at day 7 compared to wildtype, p<0.0001) but when healed these wounds had excessive collagen density and skin thickening, and abnormal collagen fibre organisation (assessed by Masson’s Trichrome staining). The post burn scars formed in 11β-HSD1 knockout mice demonstrated different skin elastic properties compared to those formed in wildtype mice. In wildtype mice application of scaffolds loaded with inactive glucocorticoid (prednisone) significantly impacted wound healing demonstrating the feasibility of using enzyme substrates to improve wound outcomes.The findings demonstrate the importance of skin 11β-HSD1 in wound healing and scarring after burn injury and indicate ways in which excessive scarring might be prevented.