Toll样受体4在对乙酰氨基酚肝损伤不同阶段肝细胞程序性坏死和再生中的作用

Previous data indicate that acetaminophen (APAP)induces hepatocyte necrosis. Our preliminary study has observed hepatocyte necroptosis, a novel programmed cell death, in APAP-treated mice. In the the present study, we hypothesize that endogenous ligand HMBG1 activates toll-like receptor 4 (TLR4) signaling and regulates hepatocyte necroptosis and regeneration during APAP-induced acute liver injury. To explore the role of TLR4 on APAP-induced hepatocyte necroptosis, we are to measure hepatocyte necroptosis in APAP-treated tlr4 mutant mice and wild type mice. To explore the role of TLR4 on hepatocyte regeneration during APAP-evoked acute liver injury, we are to measure hepatocyte proliferation during APAP-induced acute liver injury. The present study is to investigate differential role of M1 macrophage -sourced proinflammatory cytokines and M2 macrophage-sourced antiinflammatory cytokines on hepatocyte necroptosis and regeneration during APAP-induced acute liver injury. To explore whether TLR4-mediated PI3K/Akt/mTOR signaling is involved in hepatocyte regeneration during APAP-evoked acute liver injury, the present study is to investigate the effects of the PI3K and mTOR inhibitors on hepatocyte proliferation in APAP-treated mice. To further demonstrate the role of PI3K/Akt signaling on hepatocyte regeneration during APAP-induced acute liver injury, this study is also to observe hepatocyte proliferation in APAP-treated Akt-/- mice. This study will privide theoretical basis for exploring molecular mechanism of APAP-induced acute liver injury.

过去认为对乙酰氨基酚(APAP)主要引起肝细胞坏死。前期研究发现，APAP肝损伤过程伴随有肝细胞程序性坏死--一种全新的程序性死亡方式。课题组假设：APAP急性肝损伤过程释放的内源性配体（HMGB1）通过激活TLR4信号、调节肝细胞程序性坏死和再生。本课题拟对比tlr4基因突变型与野生型小鼠在APAP急性肝损伤过程肝细胞程序性坏死和增殖情况，以阐明TLR4信号在APAP肝损伤不同阶段肝细胞程序性坏死和再生中的作用；重点阐明M1型巨噬细胞TLR4下游促炎细胞因子和M2型巨噬细胞TLR4下游抗炎细胞因子在调节肝细胞程序性坏死和再生中的不同作用；通过观察PI3K抑制剂、Akt1基因敲除和mTOR抑制剂对APAP急性肝损伤不同阶段肝细胞再生的拮抗效应，进一步探讨TLR4下游PI3K-Akt-mTOR信号调控APAP急性肝损伤过程肝细胞再生的分子机理。本课题为探明APAP急性肝毒性机理提供理论依据。