Oral 63rd Endocrine Society of Australia Annual Scientific Meeting 2020

Skin glucocorticoid metabolism in burn injury: novel approaches to reduce scarring (#9)

Kevin Hung-Yueh Tsai 1 2 , Roxanne Janine Parungao 2 , Huaikai Shi 2 , Sina Naficy 3 , Ying Hui Fung 2 , Josephine Ivy Malcolm 2 , Xiaosuo Wang 4 , Zhe Li 5 , Andrea C Issler-Fisher 5 , Peter Maitz 2 5 , Mark Cooper 1 , Yiwei Wang 2
  1. Adrenal Steroid Group, ANZAC Research Institute, Sydney, NSW, Australia
  2. Burns & Reconstructive Surgery Research Group, ANZAC Research Institute, Sydney, NSW, Australia
  3. School of Chemical and Biomolecular Engineering, The University of Sydney, Sydney, NSW, Australia
  4. Bosch Mass Spectrometery Facility, Bosch Institute, Sydney, NSW, Australia
  5. Burns & Reconstructive Surgery Unit, Concord Hospital, Sydney, NSW, Australia

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 (11βHSD1). We hypothesised that skin glucocorticoid metabolism 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 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 11βHSD1 in skin to evaluate the effects of 11βHSD1 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 11βHSD1.

Expression of 11βHSD1 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 11βHSD1 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 11βHSD1 in wound healing and scarring after burn injury and indicates ways in which excessive scarring might be prevented.