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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\u2010kB activity. Combined treatment of NM\u2010exposed mice with VD3 and SP synergistically inhibited the expression of iNOS in the skin and decreased the expression of matrix metallopeptidase\u20109, C\u2010C motif chemokine ligand 2, interleukin (IL)\u20101\u03b1, and IL\u20101\u03b2. 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\u2010inflammatory 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.<\/jats:p>","DOI":"10.1111\/nyas.14485","type":"journal-article","created":{"date-parts":[[2020,9,6]],"date-time":"2020-09-06T10:12:57Z","timestamp":1599387177000},"page":"170-182","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["A novel treatment for skin repair using a combination of spironolactone and vitamin D3"],"prefix":"10.1111","volume":"1480","author":[{"given":"Dauren","family":"Biyashev","sequence":"first","affiliation":[{"name":"Department of Dermatology, Feinberg School of Medicine Northwestern University  Chicago Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ummiye V.","family":"Onay","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Feinberg School of Medicine Northwestern University  Chicago Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prarthana","family":"Dalal","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Feinberg School of Medicine Northwestern University  Chicago Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Demczuk","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Feinberg School of Medicine Northwestern University  Chicago Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Spencer","family":"Evans","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Feinberg School of Medicine Northwestern University  Chicago Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6327-3581","authenticated-orcid":false,"given":"Jos\u00e9\u2010Marc","family":"Techner","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Feinberg School of Medicine Northwestern University  Chicago Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8297-433X","authenticated-orcid":false,"given":"Kurt Q.","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Feinberg School of Medicine Northwestern University  Chicago Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,9,6]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/2013.jamadermatol.541"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1039\/9781782622413-00029"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfp253"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/nyas.13099"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2018.01453"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2018.04.001"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/jid.2015.322"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1089\/dna.2017.3978"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2017.04.040"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1080\/15569527.2017.1355315"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2019.1569298"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1159\/000486536"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2013.12.016"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00014.2015"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00590.2005"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00002.2009"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.467670"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1097\/MED.0b013e3283391989"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.115.011106"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvy092"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2016.05.101"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2016.07.025"},{"key":"e_1_2_8_24_1","first-page":"17","article-title":"Efficacy and safety of stored and newly prepared tribromoethanol in ICR mice","volume":"44","author":"Lieggi C.C.","year":"2005","journal-title":"Contemp. 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