Abstract
Use of topical glucocorticoid for inflammatory skin conditions is limited by systemic and local side-effects. This investigation addressed the hypothesis that topical 5α-tetrahydrocorticosterone (5αTHB, a corticosterone metabolite) inhibits dermal inflammation without affecting processes responsible for skin thinning and impaired wound healing. The topical anti-inflammatory properties of 5αTHB were compared with those of corticosterone in C57Bl/6 male mice with irritant dermatitis induced by croton oil, whereas its effects on angiogenesis, inflammation, and collagen deposition were investigated by subcutaneous sponge implantation. 5αTHB decreased dermal swelling and total cell infiltration associated with dermatitis similarly to corticosterone after 24h, although at a five fold higher dose, but in contrast did not have any effects after 6h. Pre-treatment with the glucocorticoid receptor antagonist RU486 attenuated the effect of corticosterone on swelling at 24h, but not that of 5αTHB. After 24h 5αTHB reduced myeloperoxidase activity (representative of neutrophil infiltration) to a greater extent than corticosterone. At equipotent anti-inflammatory doses 5αTHB suppressed angiogenesis to a limited extent, unlike corticosterone which substantially decreased angiogenesis compared to vehicle. Furthermore, 5αTHB reduced only endothelial cell recruitment in sponges whereas corticosterone also inhibited smooth muscle cell recruitment and decreased transcripts of angiogenic and inflammatory genes. Strikingly, corticosterone, but not 5αTHB, reduced collagen deposition. However, both 5αTHB and corticosterone attenuated macrophage infiltration into sponges. In conclusion, 5αTHB displays the profile of a safer topical anti-inflammatory compound. With limited effects on angiogenesis and extracellular matrix, it is less likely to impair wound healing or cause skin thinning.
Highlights
Inflammatory skin disease is highly prevalent worldwide: according to estimates published in 2012, eczema affects approximately 230 million people globally, and topical anti-inflammatory glucocorticoids are the most common treatment [1]
Skin atrophy is characterised by increased transparency and striae, due to suppression of cell proliferation and inhibition of collagen synthesis, whereas delayed wound healing is attributed to dysregulation of keratinocyte proliferation, fibroblastic activity, and angiogenesis causing delayed formation of granulation tissue [4,5]
Anti-inflammatory properties, but a safer systemic side effect profile, of 5aTHB, an A-ring reduced metabolite of corticosterone, have been demonstrated previously in vivo in a murine model of thioglycollate-induced peritonitis [7]. This investigation addressed the hypotheses that 5aTHB has advantages over conventional glucocorticoids as a topical treatment for irritant dermatitis, and that its actions are mediated through glucocorticoid receptor (GR). 5aTHB was demonstrated to be an effective topical anti-inflammatory agent in an in vivo model of irritant dermatitis induced by croton oil, with effects mainly on pathways regulating vascular permeability to cell infiltration rather than suppression of pro-inflammatory markers
Summary
Inflammatory skin disease is highly prevalent worldwide: according to estimates published in 2012, eczema affects approximately 230 million people globally, and topical anti-inflammatory glucocorticoids are the most common treatment [1]. Skin atrophy is characterised by increased transparency and striae, due to suppression of cell proliferation and inhibition of collagen synthesis, whereas delayed wound healing is attributed to dysregulation of keratinocyte proliferation, fibroblastic activity, and angiogenesis causing delayed formation of granulation tissue [4,5] These factors restrict the use of more potent glucocorticoids and the length of treatment, in vulnerable patients such as infants and the elderly. The efficacy of topical 5aTHB application for treating skin inflammation was compared with that of corticosterone in vivo using croton oil-induced dermatitis and the role of GR was assessed by pre-administration of the GR antagonist mifepristone (RU486) This is a steroid-responsive model of dermal inflammation, driven primarily by neutrophil accumulation, commonly used for testing anti-inflammatory treatments for irritant dermatitis [8,9]. An in vivo model of sponge implantation allowed comparison of the effects of corticosterone and 5aTHB on inflammation, angiogenesis and collagen deposition
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