Abstract
BackgroundFerroptosis 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.Methodswe 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.ResultsOur 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.ConclusionsThese 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.
Highlights
Ferroptosis is a new type of nonapoptotic cell death model that was closely related to reactive oxygen species (ROS) accumulation
The results showed that seawater exposure changed MLE-12 morphology (Fig. 1a) and decreased cellular viability in time-dependent manner (Fig. 1b)
Fer-1 significantly reduced the content of MDA (Fig. 2j). These results suggest that ferroptosis is involved in MLE-12 cell damage induced by seawater stimulation
Summary
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. We test the hypothesis that activation of Nrf pathway attenuates seawater drowning-induced ALI via inhibiting ferroptosis. Qiu et al Respiratory Research (2020) 21:232 cascades such as mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt tightly regulated HO1 gene expression [10]. Among these factors which can induce HO-1 expression, Nrf has a key role in regulating cellular antioxidant stress and eliminating reactive oxygen species (ROS) [11]. Whether or not Nrf is responsible for HO-1 induction in seawater-induced ALI is still unknown
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