Abstract：
Monomethyl fumarate (MMF), a potent anti-inflammatory agent used to treat multiple sclerosis, has demonstrated efficacy in various inflammatory and ischemia/reperfusion (IR) models; however, its impact on IR-induced acute lung injury (ALI) has not been explored. We investigated, for the first time, whether MMF attenuates lung IR injury through inhibition of the GAPDH/Siah1 signaling pathway. Rats were subjected to IR injury using an isolated perfused lung model, and proximity ligation assays were employed to evaluate the presence and distribution of the GAPDH/Siah1 complex. In vitro studies involved pretreating human primary alveolar epithelial cells (HPAECs) with MMF and/or inducing GAPDH overexpression or silencing, followed by exposure to hypoxia-reoxygenation. The findings revealed significantly reduced lung damage indicators, including edema, proinflammatory cytokines, oxidative stress and apoptosis, in MMF-treated rats. Notably, MMF treatment inhibited GAPDH/Siah1 complex formation and nuclear translocation, indicating that disruption of the GAPDH/Siah1 cascade was the primary cause of these improvements. Our in vitro studies on pretreated HPAECs corroborate these in vivo findings, further strengthening this interpretation. Our study results suggest that the protective effects of MMF against lung IR injury may be attributed, at least in part, to its ability to disrupt the GAPDH/Siah1 signaling cascade, thereby attenuating inflammatory and apoptotic responses. Given these encouraging results, MMF has emerged as a promising therapeutic candidate for the management of lung IR injury.
摘要：
富马酸单乙酯（MMF），一种用于治疗多发性硬化症的有效抗炎药，已在各种炎症和缺血/再灌注（IR）模型中证明了疗效；然而，其对IR诱导的急性肺损伤（ALI）的影响尚未被研究。我们调查了,第一次,MMF是否通过抑制GAPDH/Siah1信号通路减轻肺IR损伤。使用分离的灌注肺模型对大鼠进行IR损伤，和邻近连接测定用于评估GAPDH/Siah1复合物的存在和分布。体外研究涉及用MMF预处理人原代肺泡上皮细胞（HPAECs）和/或诱导GAPDH过表达或沉默，然后暴露于缺氧-复氧。研究结果表明，肺损伤指标显着降低，包括水肿,促炎细胞因子，氧化应激和细胞凋亡，在MMF处理的大鼠中。值得注意的是,MMF处理抑制GAPDH/Siah1复合物形成和核易位，表明GAPDH/Siah1级联的破坏是这些改善的主要原因。我们对预处理的HPAECs的体外研究证实了这些体内发现，进一步加强这种解释。我们的研究结果表明，MMF对肺IR损伤的保护作用可能归因于，至少在某种程度上,破坏GAPDH/Siah1信号级联的能力，从而减弱炎症和凋亡反应。鉴于这些令人鼓舞的结果，MMF已成为治疗肺IR损伤的有希望的候选药物。
