凋亡刺激蛋白 p53 的抑制剂抑制铁死亡，减轻肠缺血/再灌注引起的急性肺损伤。
Inhibitor of apoptosis-stimulating protein of p53 inhibits ferroptosis and alleviates intestinal ischemia/reperfusion-induced acute lung injury.
机构信息
Department of Critical Care Medicine, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, China.
Department of Cardiothoracic Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
出版信息
Cell Death Differ. 2020 Sep;27(9):2635-2650. doi: 10.1038/s41418-020-0528-x. Epub 2020 Mar 18.
Acute lung injury (ALI) is a life-threatening disorder with high rates of morbidity and mortality. Reactive oxygen species and epithelial apoptosis are involved in the pathogenesis of acute lung injury. Ferroptosis, an iron-dependent non-apoptotic form of cell death, mediates its effects in part by promoting the accumulation of reactive oxygen species. The inhibition of ferroptosis decreases clinical symptoms in experimental models of ischemia/reperfusion-induced renal failure and heart injury. This study investigated the roles of inhibitor of apoptosis-stimulating protein of p53 (iASPP) and Nrf2 in ferroptosis and their potential therapeutic effects in intestinal ischemia/reperfusion-induced acute lung injury. Intestinal ischemia/reperfusion-induced ALI was induced in wild-type and Nrf2 mice. The mice were treated with erastin followed by liproxstatin-1. Ferroptosis-related factors in mice with ischemia/reperfusion-induced acute lung injury or in mouse lung epithelial-2 cells with hypoxia/regeneration (HR)-induced ALI were measured by western blotting, real-time PCR, and immunofluorescence. Ferroptosis contributed to intestinal ischemia/reperfusion-induced ALI in vivo. iASPP inhibited ferroptosis and alleviated intestinal ischemia/reperfusion-induced acute lung injury, and iASPP-mediated protection against ischemia/reperfusion-induced ALI was dependent on Nrf2 signaling. HR-induced acute lung injury enhanced ferroptosis in vitro in mouse lung epithelial-2 cells, and ferroptosis was modulated after the enhancement of intestinal ischemia/reperfusion in Nrf2 mice. iASPP mediated its protective effects against acute lung injury through the Nrf2/HIF-1/TF signaling pathway. Ferroptosis contributes to intestinal ischemia/reperfusion-induced ALI, and iASPP treatment inhibits ferroptosis in part via Nrf2. These findings indicate the therapeutic potential of iASPP for treating ischemia/reperfusion-induced ALI.
急性肺损伤（ALI）是一种危及生命的疾病，发病率和死亡率都很高。活性氧和上皮细胞凋亡参与急性肺损伤的发病机制。铁死亡是一种铁依赖性非凋亡性细胞死亡形式，部分通过促进活性氧的积累来发挥作用。铁死亡的抑制可减轻缺血/再灌注诱导的肾衰竭和心脏损伤实验模型中的临床症状。本研究探讨了凋亡刺激蛋白 p53 的抑制剂（iASPP）和 Nrf2 在铁死亡中的作用及其在肠缺血/再灌注诱导的急性肺损伤中的潜在治疗作用。在野生型和 Nrf2 小鼠中诱导肠缺血/再灌注诱导的 ALI。用 erastin 处理后用 liproxstatin-1 处理。通过 Western blot、实时 PCR 和免疫荧光法测量缺血/再灌注诱导的急性肺损伤小鼠或缺氧/再生（HR）诱导的 ALI 小鼠肺上皮-2 细胞中的铁死亡相关因子。铁死亡导致体内肠缺血/再灌注诱导的 ALI。iASPP 抑制铁死亡并减轻肠缺血/再灌注诱导的急性肺损伤，iASPP 介导的对缺血/再灌注诱导的 ALI 的保护作用依赖于 Nrf2 信号。HR 在体外增强了小鼠肺上皮-2 细胞中的急性肺损伤，增强了 Nrf2 小鼠的肠缺血/再灌注后铁死亡得到了调节。iASPP 通过 Nrf2/HIF-1/TF 信号通路发挥其对急性肺损伤的保护作用。铁死亡参与肠缺血/再灌注诱导的 ALI，iASPP 治疗部分通过 Nrf2 抑制铁死亡。这些发现表明 iASPP 治疗缺血/再灌注诱导的 ALI 的治疗潜力。
Zotero 插件