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.

中文翻译：

---

一种使用螺内酯和维生素 D3 组合进行皮肤修复的新疗法

暴露于有毒化学物质对皮肤的伤害会导致炎症介质的释放和免疫细胞的募集。氮芥 (NM) 和其他烷化剂会导致严重的皮肤损伤，因此治疗选择有限。在这里，我们表明维生素 D3 (VD3) 和螺内酯 (SP)（一种盐皮质激素受体拮抗剂）的联合治疗显着改善了炎症的消退并加速了 NM 暴露后的伤口愈合。SP增强了VD3对核因子-kB活性的抑制作用。用 VD3 和 SP 联合治疗暴露于 NM 的小鼠可协同抑制皮肤中 iNOS 的表达并降低基质金属肽酶-9、​​C-C 基序趋化因子配体 2、白细胞介素 (IL)-1α 和 IL-1β 的表达。联合治疗减少了局部促炎 M1 巨噬细胞的数量，导致伤口微环境中的 M2/M1 比率增加。联合治疗后皮肤的细胞凋亡也减少。总之，这创造了一个proresolution 状态，导致更快的伤口闭合。VD3 和 SP 联合治疗可有效调节巨噬细胞中的免疫反应和激活抗炎途径以促进组织修复。总之，这些数据表明 VD3 和 SP 可能构成一种有效的治疗方案，以改善 NM 或其他皮肤化学损伤后的伤口愈合。导致更快的伤口闭合。VD3 和 SP 联合治疗可有效调节巨噬细胞中的免疫反应和激活抗炎途径以促进组织修复。总之，这些数据表明 VD3 和 SP 可能构成一种有效的治疗方案，以改善 NM 或其他皮肤化学损伤后的伤口愈合。导致更快的伤口闭合。VD3 和 SP 联合治疗可有效调节巨噬细胞中的免疫反应和激活抗炎途径以促进组织修复。总之，这些数据表明 VD3 和 SP 可能构成一种有效的治疗方案，以改善 NM 或其他皮肤化学损伤后的伤口愈合。