Sesn2通过P62-Keap1-Nrf2通路调控肺泡II型上皮细胞铁死亡在急性肺损伤中的作用及机制研究

ALI/ARDS的发病机制仍不清楚。本研究在我们以前对不同细胞死亡形式参与急性肺损伤发病机制的基础上，研究肺泡Ⅱ型上皮细胞（AEC-Ⅱ）铁死亡在ALI/ARDS中的作用，以期发现新的治疗靶点。我们前期研究发现Sesn2基因敲除使小鼠肺损伤程度和死亡率增加，并伴随肺组织和AEC-Ⅱ 中Nrf2和GPX4表达下降。我们推测：Sesn2可能通过Nrf2相关信号通路抑制AEC-Ⅱ铁死亡对急性肺损伤发挥其内源性保护作用。本项目以野生型、Sesn2基因敲除小鼠为研究对象，采用LPS气管内滴注制备ALI/ARDS模型，在体阐明Sesn2通过调控AEC-Ⅱ铁死亡在ALI/ARDS中的作用；并进一步通过原代培养野生型、Sesn2基因敲除小鼠AEC-Ⅱ和肺泡上皮细胞株MLE-12，体外证实Sesn2通过p62-Keap1-Nrf2信号轴调控铁死亡的分子机制，为ALI/ARDS寻找新的治疗靶点打下坚实理论基础。

The pathogenesis of ALI/ARDS is still unclear. In this study, we focus on the role of ferroptosis of type Ⅱ alveolar epithelial cells （AEC-Ⅱ）in ALI/ARDS on the basis of our previous involvement in the pathogenesis of acute lung injury in different cell death forms, aimed to finding new therapeutic targets. Our previous studies found that Sesn2 gene knockout increased lung injury and mortality in mice, accompanied by decreased expression of Nrf2 and GPX4 in lung tissues and AEC-Ⅱ. Therefore, we speculate that sesn2 may play an endogenous protective role in acute lung injury by inhibiting AEC-Ⅱ ferroptosis through Nrf2 related signaling pathway. With wild type, Sesn2 knockout mice as the object, this project prepares ALI/ARDS model by intratracheal instillation of LPS, to study the role of AEC-Ⅱ ferroptosis regulated by Sesn2 in pathogenesis of the ALI/ARDS in vivo. Futhermore, in vitro experiments are performed to clarify the role of Sesn2 in regulation ferroptosis through p62-Keap1-Nrf2 axis, and the upstream and downstream signal regulatory mechanism, by the primary culturing AEC-Ⅱ from wild-type and Sesn2 knockout mice and alveolar epithlial cell line MLE-12, which will lay a solid theoretical foundation for finding new therapeutic targets for ALI/ARDS.