Re-Epithelialization of Pathological Cutaneous Wounds Is Improved by Local Mineralocorticoid Receptor Antagonism.
Impaired cutaneous wound healing is a social burden. It occurs as a consequence of glucocorticoid treatment in several pathologies. Glucocorticoids (GC) bind not only to the glucocorticoid receptor but also to the mineralocorticoid receptor (MR), both expressed by keratinocytes. In addition to its beneficial effects through the glucocorticoid receptor, GC exposure may lead to inappropriate MR occupancy. We hypothesized that dermatological use of MR antagonists (MRA) might be beneficial by overcoming the negative impact of GC treatment on pathological wounds. The potent GC clobetasol, applied as an ointment to mouse skin, or added to cultured human skin explants, induced delayed wound closure and outgrowth of epidermis with reduced proliferation of keratinocytes. Delayed wound re-epithelialization was rescued by local MRA application. Normal skin was unaffected by MRA. The benefit of MR blockade is explained by the increased expression of MR in clobetasol-treated mouse skin. Blockade of the epithelial sodium channel by phenamil also rescued cultured human skin explants from GC-impaired growth of the epidermis. MRA application over post-biopsy wounds of clobetasol-treated skin zones of healthy volunteers (from the Interest of Topical Spironolactone's Administration to Prevent Corticoid-induced Epidermal Atrophy clinical trial) also accelerated wound closure. In conclusion, we propose repositioning MRA for cutaneous application to improve delayed wound closure occurring in pathology.
Laboratory of Progenitors and Endothelial Cells During and After Pregnancy, INSERM, UMR 938, Centre de Recherche St Antoine, Paris, France; Faculty of Medecine, Université Pierre et Marie Curie, Paris Sorbonne, Paris, France; Department of Basic Science, Thai Nguyen University of Agriculture and Forestry, Thainguyen, Vietnam.
Van Tuan
VT
Nguyen
Faculty of Medecine, Université Pierre et Marie Curie, Paris Sorbonne, Paris, France; Team 1, UMR 1138, INSERM, Centre de Recherche des Cordeliers, Paris, France. Electronic address: nicolette.farman@crc.jussieu.fr.
Nicolette
N
Farman
Département de Dermatologie, Assistance Publique Hôpitaux de Paris (APHP), Hôpital Bichat Claude Bernard, Paris, France; Faculty of Medecine, Université Paris Diderot, Paris Sorbonne Cité, Paris, France.
Eve
E
Maubec
Laboratory of Progenitors and Endothelial Cells During and After Pregnancy, INSERM, UMR 938, Centre de Recherche St Antoine, Paris, France; Faculty of Medecine, Université Pierre et Marie Curie, Paris Sorbonne, Paris, France.
Dany
D
Nassar
Faculty of Medecine, Université Pierre et Marie Curie, Paris Sorbonne, Paris, France; Team 2, UMR 1138, INSERM, Centre de Recherche des Cordeliers, Paris, France.
Dorinne
D
Desposito
Faculty of Medecine, Université Pierre et Marie Curie, Paris Sorbonne, Paris, France; Team 2, UMR 1138, INSERM, Centre de Recherche des Cordeliers, Paris, France.
Ludovic
L
Waeckel
Laboratory of Progenitors and Endothelial Cells During and After Pregnancy, INSERM, UMR 938, Centre de Recherche St Antoine, Paris, France; Faculty of Medicine, Université Paris Descartes-Paris 5, Paris, France; Department of Dermatology, Hôpital Cochin-Tarnier, Paris, France.
Sélim
S
Aractingi
Faculty of Medecine, Université Pierre et Marie Curie, Paris Sorbonne, Paris, France; Team 1, UMR 1138, INSERM, Centre de Recherche des Cordeliers, Paris, France.
Frederic
F
Jaisser
D000279:Administration, Cutaneous; D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002990:Clobetasol / Q000008:administration & dosage / Q000494:pharmacology*; D004817:Epidermis / Q000187:drug effects / Q000473:pathology; D005938:Glucocorticoids / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D000451:Mineralocorticoid Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D009824:Ointments; D062326:Re-Epithelialization / Q000187:drug effects*; D018161:Receptors, Mineralocorticoid / Q000187:drug effects / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000473:pathology; D014945:Wound Healing / Q000187:drug effects*
D005938:Glucocorticoids; D000451:Mineralocorticoid Receptor Antagonists; D009824:Ointments; D018161:Receptors, Mineralocorticoid; C047088:phenylamil; D000584:Amiloride; D002990:Clobetasol