急性肺损伤与II型肺泡上皮细胞功能障碍有关，死亡率极高。项目组预实验结果发现铁死亡相关基因Slc7a11和端粒酶逆转录酶TERT在急性肺损伤的Nrf2敲基因小鼠肺组织中表达下调；氧糖剥夺/复氧细胞研究中发现，下调表达Nrf2可解除SLC7A11对铁死亡抑制作用，下调TERT加重疾病组细胞铁死亡。本项目的科学假说是：Nrf2和TERT在急性肺损伤中可能通过SLC7A11抑制II型肺泡上皮细胞铁死亡从而发挥肺保护作用。基于以上科学假说，本项目拟通过Nrf2敲基因小鼠建立急性肺损伤模型，利用小鼠II型肺泡上皮细胞建立氧糖剥夺/复氧模型，研究Nrf2、TERT和SLC7A11之间的调控作用，利用同步辐射软X射线显微成像技术，观察铁在细胞内分布与含量改变，揭示Nrf2和TERT通过调节II型肺泡上皮细胞铁死亡发挥肺保护的作用机制，为确立早期临床诊断标记物及新型靶分子治疗策略提供理论基础和实验依据。

Alveolar epithelial type Ⅱ cells (AEC Ⅱ) dysfunction is closely related to acute lung injury. Our preliminary results found out that the expression of ferroptosis related gene member 11 of solute carrier family 7 (Slc7a11) and telomerase reverse transcriptase (TERT), the main component of telomerase, were down-regulated in the lung tissues of intestine ischemia reperfusion induced acute lung injury (IIR ALI) among Nrf2 gene knockout mouse compared with those in wild types; the results of oxygen-glucose deprivation and restoration (OGD/R) cell model showed that knockdown of Nrf2 abolished the inhibitory effect of SLC7A11 on OGD/R induced ferroptosis. Downregulation of TERT aggravated ferroptosis of epithelial cells in OGD/R model. The scientific hypothesis of this project is that Nrf2 and TERT may play a protective role in ALI by inhibiting ferroptosis in AEC Ⅱ through SLC7A11. Based on these scientific hypothesis, this item plan to establish animal model of IIR ALI by Nrf2 gene knockout mice, and utilize AEC Ⅱof mice to establish OGD/R cell models. By constructing the overexpression lentiviruses of Nrf2, Tert and Slc7a11 or interference lentivirus vectors, the relationships among Nrf2, TERT and SLC7A11 will be investigated, and the distribution and content changes of iron in organelle structures will be observed by synchrotron radiation soft X-ray microscopy. Additionally, the protective roles of Nrf2 and TERT in regulating ferroptosis in lung tissue will be clarified, so as to provide theoretical principles and experimental basis to establish early clinical diagnostic biomarkers and novel target molecular policies.