Jiang Yiya, Huang Zhaoshuai, Li Xianpeng, Zhou Liuzhi, Zhu Xiuping, Chen Feng, Shi Yanjun
Abdominal Transplantation Center, General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of General Practice, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Liver Transpl. 2023 Oct 1;29(10):1050-1062. doi: 10.1097/LVT.0000000000000210. Epub 2023 Jul 14.
Ischemia-reperfusion injury (IRI) remains a major cause of mortality and morbidity after liver surgery. Endoplasmic reticulum (ER) stress is a critical mechanism of inflammatory injury during hepatic IRI. In this study, we investigated the effect of sphingosine kinases 2 (SK2) on ER stress and hepatic IRI. We established hepatic IRI mice and hepatocellular hypoxia/reoxygenation in vitro model. We observed the SK2 and ER stress protein IRE1α expression. Then, we used an SK2 inhibitor and knocked down IRE1α/SK2, to observe the effect of SK2 during IRI. Our results showed that the expression of ER stress and SK2 was significantly elevated during hepatic IRI. Inhibition of SK2 ameliorated liver inflammation and reduced cell apoptosis in hepatic IRI mice. Consistently, we found that the inhibition of IRE1α also downregulated SK2 expression and reduced mitochondrial membrane permeability. Furthermore, the knockdown of SK2 could also reduce cell damage and reduce the expression of inflammatory factors but did not influence ER stress-related signaling pathway. Taken together, our results suggested that ER stress and SK2 played important and regulatory roles in hepatic IRI. Inhibition of ER stress and SK2 could significantly improve liver function after hepatic IRI.
缺血再灌注损伤（IRI）仍然是肝脏手术后死亡率和发病率的主要原因。内质网（ER）应激是肝脏IRI期间炎症损伤的关键机制。在本研究中，我们研究了鞘氨醇激酶2（SK2）对ER应激和肝脏IRI的影响。我们建立了肝脏IRI小鼠模型和体外肝细胞缺氧/复氧模型。我们观察了SK2和ER应激蛋白IRE1α的表达。然后，我们使用SK2抑制剂并敲低IRE1α/SK2，以观察SK2在IRI期间的作用。我们的结果表明，肝脏IRI期间ER应激和SK2的表达显著升高。抑制SK2可改善肝脏IRI小鼠的肝脏炎症并减少细胞凋亡。一致地，我们发现抑制IRE1α也下调了SK2的表达并降低了线粒体膜通透性。此外，敲低SK2也可减少细胞损伤并降低炎症因子的表达，但不影响ER应激相关信号通路。综上所述，我们的结果表明ER应激和SK2在肝脏IRI中发挥重要的调节作用。抑制ER应激和SK2可显著改善肝脏IRI后的肝功能。
