LICAMM Hypoxia, inflammation and local steroid metabolism during wound healing: towards a new therapy for diabetic foot ulcers

Summary

Type 2 diabetes is an unmet clinical need of global importance with a growing financial burden. Diabetic foot ulcers, characterized by chronic inflammation and hypoxia, occur in 15-25% per cent of people with diabetes (lifetime risk) and currently affect over 3 million people in the UK. Often, the lack of healing leads to amputation and strikingly up to 80% cent of people with diabetes die within five years of having an amputation or a foot ulcer.

Glucocorticoid (GC) hormones are commonly used to treat a range of inflammatory disorders and cause many adverse effects including hyperglycaemia, weight gain, skin thinning, collagen loss, impaired wound healing and increased risk of infection. GC activated by 11β-HSD1 regulate cell functions in tissues such as fat, muscle and liver but the effects of 11β-HSD1 in the skin are poorly understood. Previous research have demonstrated increased 11β-HSD1 activity during normal wound healing and improved wound healing in healthy aged mice lacking 11β-HSD1 but the role of 11β-HSD1 in wound healing impaired by diabetes has not been investigated.

Quantitative Polymerase Chain Reaction following mRNA extraction and cDNA synthesis will used to analyse gene expression during wound healing in healthy mice compared to a genetic mouse model of diabetes (leptin-receptor deficient). This will be compared to mice that have been treated with the topical 11β-HSD1 inhibitor carbenoxolone or placebo. Immunohistochemistry will be used to visualise changes in wound healing, inflammation and collagen remodelling.

The role of hypoxia will also be investigated by examining the effect of 11β-HSD1 inhibition on wound healing in the presence / absence of an impermeable dressing. This will be complimented by in vivo hypoxia experiments exploring the regulation of angiogenesis by 11β-HSD1 in primary human skin fibroblasts.

This project has the scope to develop a new treatment for diabetic foot ulcers that could improve morbidity and mortality in patients with type 2 diabetes, leading to savings in NHS expenditure of £1 billion annually.

References

Tiganescu A, Walker EA, Hardy RS, Mayes AE, Stewart PM. Localization, age- and site-dependent expression, and regulation of 11β-hydroxysteroid dehydrogenase type 1 in skin. J Invest Dermatol. 2011 Jan;131(1):30-6

Tiganescu A, Tahrani AA, Morgan SA, Otranto M, Desmouliere A, Abrahams L, Hassan-Smith Z, Walker EA, Rabbitt EH, Cooper MS, Amrein K, Lavery GG and Stewart PM. 11beta-Hydroxysteroid dehydrogenase blockade prevents age-induced skin structure and function defects. J Clin Invest. 2013, 123(7), pp.3051-60

Tiganescu A, Hupe M, Uchida Y, Mauro T, Elias PM and Holleran WM. Increased glucocorticoid activation during mouse skin wound healing. J Endocrinol. 2014, 221(1), pp.51-61

Tiganescu A, Hupe M, Uchida Y, Mauro T, Elias PM, Holleran WM. Topical 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibition Corrects Cutaneous Features of Systemic Glucocorticoid Excess in Female Mice. Endocrinology. 2018, 159(1):547-556

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