首页>
外文期刊>American Journal of Physiology
>Necrostatin-1 accelerates time to death in a rat model of cecal ligation and puncture and massively increases hepatocyte caspase-3 cleavage
【24h】
Necrostatin-1 accelerates time to death in a rat model of cecal ligation and puncture and massively increases hepatocyte caspase-3 cleavage
展开▼
机译：Necrostatin-1 accelerates time to death in a rat model of cecal ligation and puncture and massively increases hepatocyte caspase-3 cleavage
Necroptosis, a form of regulated necrosis, has been reported to be involved in numerous pathologies, including sepsis. However, a protective effect of the selective inhibitor of necroptosis, necrostatin-1 (Nec-1), against sepsis remains to be confirmed. Animals (rats and mice) were subjected to cecal ligation and puncture (CLP) to mimic clinical sepsis. Nec-1 or its vehicle (control) was administered 20 min before CLP. Survival time was observed up to 72 h after CLP. Specimens of liver tissue and serum were obtained at 6 h, 12 h, and 18 h. Expression of necroptosis-related proteins [receptor-interacting protein kinase (RIP)l, RIP3, and mixed lineage kinase domain-like (MLKL)] was determined by Western blot analysis. The RIP1/RIP3 interaction and the recruitment of MLKL to RIP3 were also analyzed. Liver function, histopathological changes, serum inflammation cyto-kines, TUNEL staining, and the expression of apoptosis-related protein, including caspase-3, B-cell lymphoma 2 (Bcl-2), and Bcl-2-associated X (Bax), was determined. As expected, Nec-1 administration reduced the expression of necroptosis-related proteins and the RIP1/RIP3 interaction, indicating inhibited necroptosis. Surprisingly, Nec-1 treatment exacerbated the liver injury and shortened survival time of septic rats with increased TUNEL-positive cells, cleaved caspase-3 protein content, and Bax/Bcl-2 ratio. Collectively, these findings show that Nec-1 administration inhibited the hepatocyte necroptosis pathway but accelerated apoptosis via the apoptotic pathway in CLP-induced sepsis rat.
展开▼
