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

  • Cell Death Differ. 2020 Sep;27(9):2635-2650. doi: 10.1038/s41418-020-0528-x.
Yingchuan Li   #  1 ,  Yongmei Cao   #  2 ,  Jian Xiao   #  3 ,  Jiawei Shang  2 ,  Qin Tan  2 ,  Feng Ping  2 ,  Weifeng Huang  2 ,  Fang Wu  2 ,  Haijun Zhang  4 ,  Xiaoping Zhang  5  6
Affiliations
  • 1. Department of Critical Care Medicine, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, China. [email protected].
  • 2. Department of Critical Care Medicine, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, China.
  • 3. Department of Cardiothoracic Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
  • 4. The Institute of Intervention Vessel, Tongji University School of Medicine, Shanghai, China. [email protected].
  • 5. The Institute of Intervention Vessel, Tongji University School of Medicine, Shanghai, China. [email protected].
  • 6. Shanghai Center of Thyroid Diseases, Tongji University School of Medicine, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 32203170 DOI: 10.1038/s41418-020-0528-x
Abstract

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.

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