Nrf2 protects against seawater drowning-induced acute lung injury via inhibiting ferroptosis
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RESEARCH
Open Access
Nrf2 protects against seawater drowninginduced acute lung injury via inhibiting ferroptosis Yu-bao Qiu1, Bin-bin Wan1, Gang Liu1, Ya-xian Wu1, Dan Chen1, Mu-dan Lu2, Jun-liang Chen1, Ren-qiang Yu2, Dao-zhen Chen2* and Qing-feng Pang1*
Abstract 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), Nrf2knockout 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, increased FTH1 and GPX4 mRNA 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. Keywords: Acute lung injury, Ferroptosis, Nrf2, Drowning, Seawater
Background Drowning is one of the main causes of accidental injury and death [1, 2]. It is estimated that more than 360,000 people die each year from drowning worldwide [3]. Moreover, it is worth noting that acute lung injury (ALI) is one of the most common complications of drowning * Correspondence: [email protected]; [email protected] 2 Central Laboratory, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, 48 Huaishu Lane, Wuxi 214122, Jiangsu Province, People’s Republic of China 1 Wuxi School of Medicine, Jiangnan University, 1800 Lihu Avenue, Wuxi 214122, Jiangsu Province, People’s Republic of China
and can develop ultimately into acute respiratory distress syndrome [4, 5]. Drowning damage alveolar epithelial cells, and thereafter cause hypoxia, hemorrhage and oxidative stress, and inflammation [6, 7]. Recent reports suggested oxidative stress played an important role in the pathogenesis drowning-induced ALI [4, 8]. Our previous studies have shown that heme oxygenase-1(HO-1) alleviated drowning-induced ALI [9]. Both several transcriptional factors (e.g. ac
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