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

Kevin H-Y Tsai; Huaikai Shi; Roxanne J Parungao; Sina Naficy; Xiaotong Ding; Xiaofeng Ding; Jonathan J Hew; Xiaosuo Wang; Wojciech Chrzanowski; Gareth G Lavery; Zhe Li; Andrea C Issler-Fisher; Jun Chen; Qian Tan; Peter K Maitz; Mark S Cooper; Yiwei Wang

doi:10.1093/burnst/tkac052

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

Burns Trauma. 2023 Jan 20:11:tkac052. doi: 10.1093/burnst/tkac052. eCollection 2023.

Authors

Kevin H-Y Tsai^{1

2}, Huaikai Shi², Roxanne J Parungao², Sina Naficy³, Xiaotong Ding⁴, Xiaofeng Ding⁵, Jonathan J Hew², Xiaosuo Wang⁶, Wojciech Chrzanowski⁷, Gareth G Lavery⁸, Zhe Li⁹, Andrea C Issler-Fisher⁹, Jun Chen⁴, Qian Tan⁵, Peter K Maitz^{2

9}, Mark S Cooper¹, Yiwei Wang^{2

4}

Affiliations

¹ Adrenal Steroid Group, ANZAC Research Institute, Concord Hospital, The University of Sydney, Sydney, NSW 2137, Australia.
² Burns and Reconstructive Surgery Research Group, ANZAC Research Institute, Concord Hospital, The University of Sydney, Sydney, NSW 2137, Australia.
³ School of Chemical and Biomolecular Engineering, The University of Sydney, Sydney, NSW 2006, Australia.
⁴ Jiangsu Provincial Engineering Research Centre of TCM External Medication Development and Application, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China.
⁵ Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital Clinical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210008, China.
⁶ Heart Research Institute, The University of Sydney, Sydney, NSW 2006 , Australia.
⁷ Sydney Nano Institute, Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia.
⁸ Department of Biosciences, Centre for Healthy Ageing and Understanding Disease, Nottingham Trent University, NG1 4BU, UK.
⁹ Burns and Reconstructive Surgery Unit, Concord Repatriation General Hospital, Sydney, NSW 2137, Australia.

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.

Keywords: 11β-HSD1 knockout; Burn injury; Drug delivery; Glucocorticoid metabolism; Polycaprolactone scaffold; Scarring; Skin 11β-HSD1; Wound healing.