Nrf2 protects against seawater drowning-induced acute lung injury via inhibiting ferroptosis
Nrf2 protects against seawater drowning-induced acute lung injury via inhibiting ferroptosis
复制标题
Nrf2通过抑制铁死亡来预防海水溺水引起的急性肺损伤
DOI：
10.1186/s12931-020-01500-2
复制
发表时间：
2020-09-09
影响因子：
5.8
通讯作者：
Pang, Qing-feng
中科院分区：
文献类型：
--
作者：
Qiu, Yu-bao;Wan, Bin-bin;Pang, Qing-feng
背景铁凋亡是一种新型的非凋亡性细胞死亡模型，与活性氧（ROS）的积累密切相关。海水淹溺引起的急性肺损伤（ALI）是由严重的氧化应激损伤引起的，已成为世界范围内意外死亡的主要原因。最新的研究表明，核因子（红细胞衍生2）样2（Nrf 2）抑制铁凋亡，维持细胞氧化还原平衡。在这里，我们测试的假设，激活Nrf 2途径减弱海水溺水诱导的ALI通过抑制铁凋亡。方法采用Nrf 2特异性激动剂富马酸二甲酯（dimethyl fumarate）、Nrf 2抑制剂ML 385、Nrf 2基因敲除小鼠和铁凋亡抑制剂Ferrostatin-1，研究Nrf 2在海水淹溺性ALI中的作用及其机制。结果Nrf 2激活剂富马酸二甲酯可提高MLE-12细胞活力，降低细胞内ROS和脂质ROS水平，阻止谷胱甘肽耗竭和脂质过氧化物蓄积，增加FTH 1和GPX 4 mRNA表达，维持线粒体膜电位。然而，ML 385在MLE-12细胞中促进细胞死亡和脂质ROS产生。此外，海水溺水后，Nrf 2基因敲除小鼠的肺损伤比WT小鼠更严重。结论Nrf 2可抑制铁凋亡，从而减轻海水淹溺所致的ALI。Nrf 2抑制铁凋亡的有效性为海水溺水诱导的ALI提供了新的治疗靶点。
Background Ferroptosis is a new type of nonapoptotic cell death model that was closely related to reactive oxygen species (ROS) accumulation. Seawater drowning-induced acute lung injury (ALI) which is caused by severe oxidative stress injury, has been a major cause of accidental death worldwide. The latest evidences indicate nuclear factor (erythroid-derived 2)-like 2 (Nrf2) suppress ferroptosis and maintain cellular redox balance. Here, we test the hypothesis that activation of Nrf2 pathway attenuates seawater drowning-induced ALI via inhibiting ferroptosis. Methods we performed studies using Nrf2-specific agonist (dimethyl fumarate), Nrf2 inhibitor (ML385), Nrf2-knockout mice and ferroptosis inhibitor (Ferrostatin-1) to investigate the potential roles of Nrf2 on seawater drowning-induced ALI and the underlying mechanisms. Results Our data shows that Nrf2 activator dimethyl fumarate could increase cell viability, reduced the levels of intracellular ROS and lipid ROS, prevented glutathione depletion and lipid peroxide accumulation, increasedFTH1andGPX4mRNA expression, and maintained mitochondrial membrane potential in MLE-12 cells. However, ML385 promoted cell death and lipid ROS production in MLE-12 cells. Furthermore, the lung injury became more aggravated in the Nrf2-knockout mice than that in WT mice after seawater drowning. Conclusions These results suggested that Nrf2 can inhibit ferroptosis and therefore alleviate ALI induced by seawater drowning. The effectiveness of ferroptosis inhibition by Nrf2 provides a novel therapeutic target for seawater drowning-induced ALI.