Ferrostatin-1 alleviates ventilator-induced lung injury by inhibiting ferroptosis
Ferrostatin-1 alleviates ventilator-induced lung injury by inhibiting ferroptosis
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DOI：
10.1016/j.intimp.2023.110356
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发表时间：
2023-05-25
影响因子：
5.6
通讯作者：
Pan, Linghui
中科院分区：
文献类型：
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作者：
Ling, Maoyao;Ye, Liu;Pan, Linghui
呼吸机致肺损伤（VILI）已成为临床上越来越常见的机械通气并发症。先前的研究表明，VILI是对级联炎症反应的结果；然而，涉及的炎症机制尚不清楚。作为一种新发现的细胞死亡形式，铁凋亡可以释放损伤相关分子（DAMPs）来触发和放大炎症反应，并参与多种炎症性疾病。本研究旨在研究先前未被认识到的铁下垂在VILI中的作用。建立小鼠VILI模型和循环拉伸（CS）诱导肺上皮细胞损伤模型。小鼠和细胞用铁凋亡抑制剂铁素-1预处理。然后采集肺组织和细胞以测定肺损伤、炎症反应、与铁下垂相关的指标和蛋白表达。与对照组相比，高潮气量（HTV）作用4 h小鼠表现出更严重的肺水肿、炎症和铁下垂激活。铁-1可显著改善VILI小鼠的组织学损伤和炎症，减轻c诱导的肺上皮细胞损伤。在机制上，铁素-1在体外和体内均显著限制了铁上吊的激活并恢复了SLC7A11/GPX4轴的功能，从而表明其作为VILI的新治疗靶点的潜力。
Ventilator-induced lung injury (VILI) has become an increasingly common complication in the clinic concerning mechanical ventilation. Previous research showed that VILI is the result of a response to cascade inflammation; however, the inflammatory mechanism involved remains unclear. As a newly recognized form of cell death, ferroptosis can release damage-related molecules (DAMPs) to trigger and amplify the inflammatory response and is involved in several inflammatory diseases. The present study aimed to investigate a previously unrecognized role of ferroptosis in VILI. A mouse model of VILI and a model of cyclic stretching (CS)-induced lung epithelial cell injury were established. Mice and cells were pretreated with ferrostain-1, an inhibitor of ferroptosis. Lung tissue and cells were then harvested to determine lung injury, inflammatory responses, indicators and protein expression associated with ferroptosis. Compared to the control group, mice subjected to high tidal volumes (HTV) for 4 h showed more severe pulmonary edema and inflammation and the activation of ferroptosis. Ferrostain-1 significantly ameliorated histological injury and inflammation in the VILI mouse and alleviated CSinduced lung epithelial cell injury. Mechanistically, ferrostain-1 markedly limited the activation of ferroptosis and recovered functionality of the SLC7A11/GPX4 axis both in vitro and in vivo, thus demonstrating its potential as a novel therapeutic target for VILI.