Department of Surgery, The Ohio State University, Columbus, Ohio, USA.
Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, USA.
J Cell Mol Med. 2022 Apr;26(7):1886-1895. doi: 10.1111/jcmm.16917. Epub 2022 Feb 24.
Nitrogen mustard (NM) is an alkylating vesicant that causes severe pulmonary injury. Currently, there are no effective means to counteract vesicant-induced lung injury. MG53 is a vital component of cell membrane repair and lung protection. Here, we show that mice with ablation of MG53 are more susceptible to NM-induced lung injury than the wild-type mice. Treatment of wild-type mice with exogenous recombinant human MG53 (rhMG53) protein ameliorates NM-induced lung injury by restoring arterial blood oxygen level, by improving dynamic lung compliance and by reducing airway resistance. Exposure of lung epithelial and endothelial cells to NM leads to intracellular oxidative stress that compromises the intrinsic cell membrane repair function of MG53. Exogenous rhMG53 protein applied to the culture medium protects lung epithelial and endothelial cells from NM-induced membrane injury and oxidative stress, and enhances survival of the cells. Additionally, we show that loss of MG53 leads to increased vulnerability of macrophages to vesicant-induced cell death. Overall, these findings support the therapeutic potential of rhMG53 to counteract vesicant-induced lung injury.
氮芥（NM）是一种烷化剂，会导致严重的肺损伤。目前，尚无有效的方法来对抗致疱剂引起的肺损伤。MG53 是细胞膜修复和肺保护的重要组成部分。在这里，我们发现 MG53 缺失的小鼠比野生型小鼠更容易受到 NM 诱导的肺损伤。用外源性重组人 MG53（rhMG53）蛋白治疗野生型小鼠可通过恢复动脉血氧水平、改善动态肺顺应性和降低气道阻力来减轻 NM 诱导的肺损伤。肺上皮细胞和内皮细胞暴露于 NM 会导致细胞内氧化应激，从而损害 MG53 的内在细胞膜修复功能。应用于培养基中的外源性 rhMG53 蛋白可保护肺上皮细胞和内皮细胞免受 NM 诱导的膜损伤和氧化应激，并提高细胞的存活率。此外，我们发现 MG53 的缺失会导致巨噬细胞对致疱剂诱导的细胞死亡更加敏感。总的来说，这些发现支持 rhMG53 治疗致疱剂引起的肺损伤的潜力。
