The most common and severe complication of burn injury is excessive scarring/tissue fibrosis. No current treatments reduce scarring after burns. Prolonged exposure to high levels of glucocorticoids (Cushing’s syndrome) detrimentally impacts skin, with reduced collagen production and impaired wound healing. We previously demonstrated that skin can generate active glucocorticoids locally through expression and activity of the 11β-hydroxysteroid dehydrogenase type 1 enzyme (11βHSD1). We hypothesised that local glucocorticoid activation by 11βHSD1 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). We utilised mice with genetic or pharmacological deletion of 11βHSD1 in skin to evaluate effects of 11βHSD1 on burn injury healing and wound fibrosis. We also developed slow release scaffolds containing therapeutic agents that are selectively reactivated in skin cells expressing 11βHSD1.
Expression of 11βHSD1 in human and mouse skin increased substantially after burn injury (7.1±1.8 fold increase on days 4-9 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 11βHSD1 deletion experienced faster wound healing post burn (45±3% wound area healed compared to 28±4% wildtype at day 7, p<0.001) but when healed these wounds had excessive collagen density and skin thickening, and highly abnormal collagen fibre organisation. In wildtype mice application of scaffolds loaded with inactive glucocorticoid (prednisone) significantly impacted wound healing demonstrating feasibility of using enzyme substrates to improve wound outcomes.
The findings demonstrate the importance of skin 11βHSD1 in wound healing and scarring after burn injury and indicate approaches to prevent excessive scarring.