Abstract
The regulation of various types of cell death may help to restore the normal physiological function of cells and play a protective role in sepsis.In the current study,we explore the role of programmed cell necrosis in sepsis and the underlying mechanisms.The septic rat model is established by Cecal-ligation and perforation(CLP),and the in vitro model is established by LPS in IEC-6 cells.Our results demonstrate that receptor-interacting protein 1(RIP1)is significantly upregulated in the ileum of septic rats and LPS-treated IEC-6 cells at both the mRNA and protein levels.Nec-1,an inhibitor of RIP1,reduces the protein levels of RIP1,p-RIP3,and phosphorylated mixed-lineage kinase domain-like(MLKL)(serine 358)and relieves intestinal injury in CLP-induced septic rats with decreased IL-6 and TNF-α levels.The in vitro experiments further reveal that LPS induces the colocalization of RIP1 and RIP3,resulting in the phosphorylation and translocation of MLKL to the plasma membrane in IEC-6 cells.LPS also facilitates ROS production in IEC-6 cells,but this effect is further reversed by Nec-1,si-RIP1 and si-RIP3.Furthermore,LPS-induced necrosis in IEC-6 cells is counteracted by NAC.Thus,we conclude that RIP1/RIP3-dependent programmed cell necrosis participates in intestinal injury in sepsis and may be associated with RIP1/RIP3-mediated ROS.
基金项目
Natural Science Foundation of Fujian Province Supported Project(2021J011318)
Fujian Provincial Clinical Medical Research Center for First Aid and Rehabilitation in Orthopaedic Trauma,Fujian,China(2020Y2014)
国家科技期刊平台
NSTL
万方数据