A novel treatment for skin repair using a combination of spironolactone and vitamin D3

• Published in: Annals of the New York Academy of Sciences Vol. 1480; no. 1; pp. 170 - 182
• Main Authors: Biyashev, Dauren, Onay, Ummiye V., Dalal, Prarthana, Demczuk, Michael, Evans, Spencer, Techner, José‐Marc, Lu, Kurt Q.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01-11-2020; John Wiley and Sons Inc
• Subjects: Alkylating agents; Alkylation; Animals; Apoptosis; Apoptosis - drug effects; Chemokines; Cholecalciferol - pharmacology; Combined treatment; Exposure; Female; Gene Expression Regulation - drug effects; Immune response; Immune system; Inflammation; Interleukins; Macrophages; Macrophages - metabolism; Macrophages - pathology; Matrix metalloproteinases; Mechlorethamine - toxicity; Metalloproteinase; Mice; Mustard; Nitric-oxide synthase; nitrogen mustard; Original; RAW 264.7 Cells; Repair; Skin; Skin - injuries; Skin - metabolism; Skin - pathology; skin injury; spironolactone; Spironolactone - pharmacology; vitamin D; Vitamin D3; Wound healing; Wound Healing - drug effects; Wounds and Injuries - chemically induced; Wounds and Injuries - drug therapy; Wounds and Injuries - metabolism; Wounds and Injuries - pathology; nitrogen mustard; spironolactone; vitamin D; skin injury
• ISSN: 0077-8923; 1749-6632
• DOI: 10.1111/nyas.14485

Injury of the skin from exposure to toxic chemicals leads to the release of inflammatory mediators and the recruitment of immune cells. Nitrogen mustard (NM) and other alkylating agents cause severe cutaneous damage for which there are limited treatment options. Here, we show that combined treatment of vitamin D3 (VD3) and spironolactone (SP), a mineralocorticoid receptor antagonist, significantly improves the resolution of inflammation and accelerates wound healing after NM exposure. SP enhanced the inhibitory effect of VD3 on nuclear factor‐kB activity. Combined treatment of NM‐exposed mice with VD3 and SP synergistically inhibited the expression of iNOS in the skin and decreased the expression of matrix metallopeptidase‐9, C‐C motif chemokine ligand 2, interleukin (IL)‐1α, and IL‐1β. The combined treatment decreased the number of local proinflammatory M1 macrophages resulting in an increase in the M2/M1 ratio in the wound microenvironment. Apoptosis was also decreased in the skin after combined treatment. Together, this creates a proresolution state, resulting in more rapid wound closure. Combined VD3 and SP treatment is effective in modulating the immune response and activating anti‐inflammatory pathways in macrophages to facilitate tissue repair. Altogether, these data demonstrate that VD3 and SP may constitute an effective treatment regimen to improve wound healing after NM or other skin chemical injury.
Our results demonstrate that vitamin D3 in combination with spironolactone treatment improves wound healing after nitrogen mustard (NM) exposure by modulating the immune response and activating anti‐inflammatory pathways. In addition to supportive treatment, this may expand the currently limited treatment options to improve clinical outcomes for NM injury.