MitoQ alleviates LPS-mediated acute lung injury through regulating Nrf2/ Drp1 pathway
MitoQ alleviates LPS-mediated acute lung injury through regulating Nrf2/ Drp1 pathway
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MitoQ通过调节Nrf2/Drp1通路减轻LPS介导的急性肺损伤
DOI：
10.1016/j.freeradbiomed.2021.01.045
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发表时间：
2021-02-05
影响因子：
7.4
通讯作者：
Wang, Xiangrui
中科院分区：
文献类型：
--
作者：
Hou, Lei;Zhang, Jinyuan;Wang, Xiangrui
脂多糖（LPS）可引起肺泡上皮细胞（AEC）凋亡和屏障破坏，是急性肺损伤（ALI）和急性呼吸窘迫综合征的特征。本研究旨在探讨线粒体醌（MitoQ）是否可以减轻LPS诱导的AEC损伤及其机制。在体外研究AEC A549细胞系中，我们注意到LPS可以诱导动力蛋白相关蛋白1（Drp 1）介导的线粒体分裂、AEC凋亡和屏障破坏，这些可以被MitoQ和线粒体分裂抑制剂1处理逆转。此外，MitoQ的保护作用随着Drp 1过表达而减弱。核因子E2相关因子2（Nrf 2）下调可通过降低LPS处理的AEC中Nrf 2靶基因如血红素加氧酶-1（HO-1）和NAD（P）H：醌氧化还原酶1（NQO 1）的表达来阻断MitoQ的作用。LPS处理的A549细胞中Nrf 2基因敲低阻止了MitoQ减少Drp 1介导的线粒体分裂、AEC凋亡和屏障破坏的保护作用。在LPS诱导的ALI小鼠模型中，MitoQ通过调节Drp 1介导的线粒体分裂、AEC凋亡和屏障破坏来进一步证实肺保护作用。此外，MitoQ的保护作用被Nrf 2抑制剂ML 385抑制。因此，我们得出结论，MitoQ通过防止Nrf 2/Drp 1介导的线粒体分裂，AEC凋亡以及屏障破坏来发挥ALI保护作用。
Lipopolysaccharide (LPS) has been known to cause alveolar epithelial cell (AEC) apoptosis and barrier breakdown that characterize acute lung injury (ALI) and acute respiratory distress syndrome. We aimed to investigate whether mitoquinone (MitoQ), a mitochondria-targeted antioxidant, could alleviate LPS-induced AEC damage in ALI and its underlying mechanisms. In vitro studies in AEC A549 cell line, we noted that LPS could induce dynamin-related protein 1 (Drp1)-mediated mitochondrial fission, AEC apoptosis and barrier breakdown, which could be reversed with MitoQ and mitochondrial division inhibitor 1 treatment. Moreover, the protective role of MitoQ was attenuated with Drp1 overexpression. Nuclear factor E2-related factor 2 (Nrf2) downregulation could block the effect of MitoQ by decreasing the expression of Nrf2 target genes in LPS-treated AEC, such as heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1). Nrf2 gene knockdown in LPS-treated A549 cells prevented the protective effect of MitoQ from decreasing Drp1-mediated mitochondrial fission, AEC apoptosis and barrier breakdown. The lung protective effect of MitoQ by regulating the Drp1-mediated mitochondrial fission, AEC apoptosis and barrier breakdown was further confirmed in vivo with LPS-induced ALI mouse model. Additionally, the protective effect of MitoQ was inhibited by Nrf2 inhibitor ML385. We therefore conclude that MitoQ exerts ALI-protective effects by preventing Nrf2/Drp1-mediated mitochondrial fission, AEC apoptosis as well as barrier breakdown.