Inhibitor of apoptosis-stimulating protein of p53 inhibits ferroptosis and alleviates intestinal ischemia/reperfusion-induced acute lung injury

被引：460

作者：

Li, Yingchuan ^{[1
]}

Cao, Yongmei ^{[1
]}

Xiao, Jian ^{[2
]}

Shang, Jiawei ^{[1
]}

Tan, Qin ^{[1
]}

Ping, Feng ^{[1
]}

Huang, Weifeng ^{[1
]}

Wu, Fang ^{[1
]}

Zhang, Haijun ^{[3
]}

Zhang, Xiaoping ^{[3
,4
]}

机构：

[1] Shanghai Jiao Tong Univ Affiliated Peoples Hosp 6, Dept Crit Care Med, Shanghai, Peoples R China

[2] Second Mil Med Univ, Changzheng Hosp, Dept Cardiothorac Surg, Shanghai, Peoples R China

[3] Tongji Univ, Inst Intervent Vessel, Sch Med, Shanghai, Peoples R China

[4] Tongji Univ, Shanghai Ctr Thyroid Dis, Sch Med, Shanghai, Peoples R China

来源：

CELL DEATH AND DIFFERENTIATION | 2020年 / 27卷 / 09期

基金：

上海市自然科学基金;

关键词：

CELL-DEATH; PATHOGENESIS; TRANSFERRIN;

D O I：

10.1038/s41418-020-0528-x

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：2635 / 2650

页数：16

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