Dr Kevin Hung-yueh Tsai^1,2, Dr Huaikai  Shi², Miss Roxanne  Parungao², Dr Sina  Naficy³, Dr Xiaosuo  Wang⁴, Dr Zhe  Li⁵, Dr  Andrea  Issler-Fisher⁵, Prof Peter  Maitz^2,5, Prof Mark  Cooper¹, Prof Yiwei Wang²

¹Adrenal Steroid Group, ANZAC Research Institute , Concord, Australia, ²Burns and Reconstructive Surgery Research Group, ANZAC Research Institute , Concord, Australia, ³School of Chemical and Biomolecular Engineering, The University of Sydney, Camperdown, Australia, ⁴Bosch Mass Spectrometry Facility, Bosch Institute, The University of Sydney, Camperdown, Australia, ⁵Burns & Reconstructive Surgery Unit, Concord Hospital, Concord, Australia

Abstract:

The development of excessive scarring and fibrosis have become the most severe and common complications of burn injury. Current treatments have limited effect on postburn scarring. Prolonged exposure to high levels of glucocorticoids (Cushing’s syndrome) detrimentally impacts on skin, leading to skin thinning and impaired wound healing. A major source of glucocorticoids in skin is local production by 11β-hydroxysteroid dehydrogenase type 1 enzyme (11β-HSD1). We hypothesised that skin glucocorticoid metabolism 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 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 and wound fibrosis. We also developed slow release scaffolds containing therapeutic agents including inactive glucocorticoids (prednisone) that are selectively reactivated in skin cells expressing 11β-HSD1.

Expression of 11β-HSD1 in human and mouse skin increased substantially after burn injury (7.1±1.8-fold increase on day 4-9 compared to non-burn skin, p<0.05). 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 healed wounds had excessive collagen density, myofibroblast accumulation and skin stiffness and strength (359±57 kPa tensile strength wildtype compared to 513±88 kPa KO, p<0.05). In wildtype mice application of scaffolds loaded with inactive glucocorticoid (prednisone) significantly reduced scar size, myofibroblast differentiation and collagen production, demonstrating 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 indicates ways in which excessive scarring might be prevented.

Biography:

Dr Kevin Tsai is a Postdoctoral Research Associate in the Burns Research Group, ANZAC Research Institute. He obtained his PhD in 2021 from the University of Sydney. His PhD thesis was to investigate the importance of 11β-HSD1 enzyme regulated skin glucocorticoid metabolism in burn wound healing and postburn scar development.