The 2nd department of Critical Care Medicine, Xi'an Chest Hospital, 710061, Xi'an, Shaanxi, China.
Department of Respiratory Medicine, Shaanxi Provincial People's Hospital, Xi'an, China.
J Mol Histol. 2022 Apr;53(2):503-510. doi: 10.1007/s10735-022-10064-y. Epub 2022 Mar 5.
Acute lung injury (ALI) is characterized with a high rate of morbidity and mortality. The injury and apoptosis of lung epithelial cells play crucial roles in the progression of ALI. Mixed lineage kinase 3 (MLK3) has been reported to be involved in the regulation of cellular biological functions, such as cell proliferation, apoptosis and ferroptosis. However, the effect of MLK3 exerted on ALI has not been reported. Here, LPS-stimulated MLE12 pulmonary epithelial cells were used as an in vitro model for ALI. In this research, LPS elevated the expression of MLK3 in MLE12 cells. The silence of MLK3 alleviated LPS-induced cell injury. Notably, LPS promoted ferroptosis through enhancing GSH depletion and the productions of MDA and iron, which was attenuated by MLK3 knockdown. Moreover, the silence of MLK3 inhibited p53 expression in LPS-induced cells along with a decrease in the expressions of p21 and Bax, while overexpressing p53 reversed these effects of MLK3 silence. Meanwhile, p53 overexpression reversed the positive effects of MLK3 knockdown on LPS-induced cell ferroptosis and injury. Together, our results confirmed that the silence of MLK3 alleviated LPS-induced lung epithelial cell injury by inhibiting p53-mediated ferroptosis.
急性肺损伤（ALI）的发病率和死亡率均较高。肺上皮细胞的损伤和凋亡在 ALI 的进展中起着关键作用。混合谱系激酶 3（MLK3）已被报道参与细胞生物功能的调节，如细胞增殖、凋亡和铁死亡。然而，MLK3 对 ALI 的影响尚未见报道。在这里，LPS 刺激的 MLE12 肺上皮细胞被用作 ALI 的体外模型。在这项研究中，LPS 上调了 MLE12 细胞中 MLK3 的表达。MLK3 的沉默减轻了 LPS 诱导的细胞损伤。值得注意的是，LPS 通过增强 GSH 耗竭以及 MDA 和铁的产生来促进铁死亡，而 MLK3 的敲低则减弱了这一作用。此外，沉默 MLK3 抑制了 LPS 诱导的细胞中 p53 的表达，并降低了 p21 和 Bax 的表达，而过表达 p53 则逆转了 MLK3 沉默的这些作用。同时，p53 的过表达逆转了 MLK3 敲低对 LPS 诱导的细胞铁死亡和损伤的正向作用。总之，我们的结果证实，沉默 MLK3 通过抑制 p53 介导的铁死亡来减轻 LPS 诱导的肺上皮细胞损伤。
