Wedelolactone inhibits ferroptosis and alleviates hyperoxia-induced acute lung injury via the Nrf2/HO-1 signaling pathway.

Hyperoxia-induced acute lung injury (HALI) is a complication of oxygen therapy. Ferroptosis is a vital factor in HALI. This paper was anticipated to investigate the underlying mechanism of Wedelolactone (WED) on ferroptosis in HALI. The current study used hyperoxia to injure two models, one HALI mouse model and one MLE-12 cell injury model. We found that WED treatment attenuated HALI by decreasing the lung injury score and lung wet/dry weight ratio and alleviating pathomorphological changes. Then, the inflammatory reaction and apoptosis in HALI mice and hyperoxia-mediated MLE-12 cells were inhibited by WED treatment. Moreover, WED alleviated ferroptosis with less iron accumulation and reversed expression alterations of ferroptosis markers, including MDA, GSH, GPX4, SLC7A11, FTH1, and TFR1 in hyperoxia-induced MLE-12 cells in vitro and in vivo. Nrf2-KO mice and Nrf2 inhibitor (ML385) decreased WED's ability to protect against apoptosis, inflammatory response, and ferroptosis in hyperoxia-induced MLE-12 cells. Collectively, our data highlighted the alleviatory role of WED in HALI by activating the Nrf2/HO-1 pathway.

ROS-mediated MAPK activation aggravates hyperoxia-induced acute lung injury by promoting apoptosis of type II alveolar epithelial cells via the STAT3/miR-21-5p axis.

Inhibition of type II alveolar epithelial (AE-II) cell apoptosis is a critical way to cure hyperoxia-induced acute lung injury (HALI). It has been reported that miR-21-5p could reduce H2O2-induced apoptosis in AE-II cells. However, the upstream molecular mechanism remains unclear. Herein, we established a cellular model of HALI by exposing AE-II cells to H2O2 treatment. It was shown that miR-21-5p alleviated H2O2-induced apoptosis in AE-II cells. ROS inhibition decreased apoptosis of H2O2-evoked AE-II cells via increasing miR-21-5p expression. In addition, ROS induced MAPK and STAT3 phosphorylation in H2O2-treated AE-II cells. MAPK inactivation reduces H2O2-triggered AE-II cell apoptosis. MAPK activation inhibits miR-21-5p expression by promoting STAT3 phosphorylation in H2O2-challenged AE-II cells. Furthermore, STAT3 activation eliminated MAPK deactivation-mediated inhibition on the apoptosis of AE-II cells under H2O2 condition. In conclusion, ROS-mediated MAPK activation promoted H2O2-triggered AE-II cell apoptosis by inhibiting miR-21-5p expression via STAT3 phosphorylation, providing novel targets for HALI treatment.