IRE1α-XBP-1通路调控Nrf2促进肺泡上皮细胞铁死亡在VILI中的机制研究

呼吸机相关性肺损伤（VILI）是由多种因素导致瀑布式炎症级联反应的结果。铁死亡是一种新型程序性细胞坏死，可触发坏死性炎症反应导致机体炎症信号放大。铁死亡是否参与VILI，目前尚不清楚。前期研究发现，内质网应激IRE1α通路参与VILI肺泡上皮细胞炎症反应，且下游XBP-1s蛋白的增加与Nrf2蛋白降解存在相关性。已知Nrf2是细胞铁死亡的关键调节因子。因此，我们提出假说：机械牵张导致肺泡上皮细胞内质网应激，IRE1α-XBP-1通路激活，XBP-1s促进Nrf2泛素化降解启动细胞铁死亡，发生瀑布式炎症联级反应，导致VILI。本项目拟从细胞、组织、动物水平等多层面探讨肺泡上皮细胞铁死亡与VILI的相关性，研究IRE1α-XBP-1信号通路是否参与VILI小鼠肺泡上皮细胞铁死亡，阐明XBP-1s是否促进Nrf2泛素化降解启动细胞铁死亡，为有效防治VILI提供新的理论依据。

Ventilator-induced lung injury (VILI) is the result of cascade inflammatory response caused by many factors. Ferroptosis is a novel type of programmed cell necrosis, which can trigger necroinflammation and amplify inflammatory signal. Whether ferroptosis is involved in VILI remains unclear. Our previous study found that endoplasmic reticulum stress IRE1 α pathway is involved in the inflammatory response of alveolar epithelial cells in VILI, and the increase of downstream XBP-1s protein is related to Nrf2 protein degradation. NRF2 is known to be a key regulator of ferroptosis. Therefore, we propose a hypothesis: mechanical stretch leads to endoplasmic reticulum stress and IRE1α-XBP-1 pathway activation. XBP-1s promotes Nrf2 ubiquitination degradation which initiates ferroptosis, producing cascade inflammatory response, leading to VILI. This project aims to explore the correlation between ferroptosis of alveolar epithelial cells and VILI, to study whether the IRE1 α - XBP-1 signaling pathway is involved in ferroptosis of alveolar epithelial cells in VILI mice, to clarify whether the XBP-1s promotes Nrf2 ubiquitination degradation which initiates ferroptosis in vivo and in vitro. This study will provide a new idea for the prevention and treatment of VILI.