4.7 Article

Isoliquiritin apioside relieves intestinal ischemia/reperfusion-induced acute lung injury by blocking Hif-1α-mediated ferroptosis

期刊

INTERNATIONAL IMMUNOPHARMACOLOGY
卷 108, 期 -, 页码 -

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ELSEVIER
DOI: 10.1016/j.intimp.2022.108852

关键词

Isoliquiritin apioside; Hif-1?; Ferroptosis; Intestinal ischemia; reperfusion; Acute lung injury

资金

  1. Key Laboratory Opening Project of Hubei Province [2021KFY052]

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This study discovered that Isoliquiritin apioside (IA) can protect against intestinal ischemia/reperfusion (I/R)-induced acute lung injury (ALI) by reducing lung epithelial ferroptosis in a Hif-1 alpha dependent manner.
Isoliquiritin apioside (IA), a critical ingredient of Glycyrrhizae radix et rhizoma, has been unveiled to possess remarkable pharmacological activity against oxidative stress and inflammation. However, the potential roles of IA in intestinal ischemia/reperfusion (I/R)-induced acute lung injury (ALI) have not been reported yet. In the present study, we explored the effects of IA on I/R-induced ALI, and also clarified the possible mechanisms. To mimic intestinal I/R-induced ALI, the mice were subjected to 60 min of intestinal ischemia via clamping of the superior mesenteric artery followed by 60 min of reperfusion. IA was administered orally (20 mg/kg/day and 50 mg/kg/day) for 7 consecutive days before intestinal I/R. Lung epithelial MLE-2 cells were subjected to hypoxia for 2 h and regeneration for 3 h to mimic in vitro ALI. The results showed that IA administration prevented intestinal I/R-induced lung injury, inflammation and edema. Also, IA administration decreased the level of ferroptosis in murine lung tissues challenged with intestinal I/R. In terms of mechanism, IA administration inhibited the protein upregulation of Hif-1 alpha and HO-1 in mice with ALI. In vitro experiments further demonstrated that IA treatment could inhibit the mRNA and protein levels of Hif-1 alpha in hypoxia/regeneration (H/R)induced MLE-2 cells in a concentration-dependent manner. Hif-1 alpha stabilizer molidustat itself also significantly promoted ferroptosis of MLE-2 cells. And Hif-1 alpha activation increased the mRNA levels of Ptgs2 and Acsl4 but decreased the mRNA level of Gpx4 in H/R-induced MLE-2 cells treated with IA. Taken together, our study unveiled IA could protect against intestinal I/R-induced ALI by decreasing lung epithelial ferroptosis in a Hif-1 alpha dependent manner.

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