Mechanism of vulnerability to endotoxin of regenerating liver and its treatment

背景资料。血小板活化因子(PAF)在脂多糖(LPS)诱导的再生大鼠肝损伤的发病机制中起重要作用。内毒素和PPAF均激活核因子-kB，核因子-kB是肿瘤坏死因子-α和细胞因子诱导的中性粒细胞趋化因子的关键转录因子。本研究的目的是探讨PAF如何参与内毒素诱导和核因子-kB介导的大鼠肝脏再生过程中对肿瘤坏死因子-α和肿瘤坏死因子受体的调节。术后46小时，70%肝切除大鼠和假手术大鼠静脉注射脂多糖(1.5 mg/kg)。仅在肝切除大鼠，脂多糖可致大鼠高死亡率，肝组织散在坏死，并有CINC阳性中性粒细胞浸润，CINC信使RNA持续上调和激活肝脏中的NF-kB。使用PAF受体拮抗剂TCV-309可有效地预防这些现象的发生。肝切除后4h，肝细胞、枯否细胞和中性粒细胞中均可见核因子-kB的表达，表明该因子在这些细胞中处于激活状态。根据这些结果，我们认为PAD通过中性粒细胞的积聚和激活参与了CINC的持续上调和NF-kB的激活，从而参与了内毒素诱导的再生大鼠肝损伤。

Background. Platelet-activating factor (PAF) has been shown to be an important mediator in the pathogenesis of lipopolysaccharide (LPS)-induced liver ijury in regenerating rat livers. Both LPS and PPAF activate nuclear factor-kappa B (NF-kB), a key transcription factor for tumor necrosis factor-a (TNF-a) and cytokine-induced neutrophil attractant (CINC). The aim of this study is to investigate how PAF participates in the LPS-induced and NF-kB-mediated regulation of TNF-a and CINCin regenerating rat livers.Methods. LPS (1.5 mg/kg) was intravenously administered into 70 % hepatectomized rats and sham-operated rats 46 hours postoperatively.Results. LPS administration caused a high mortality rate, scattered necrosis in the liver with infiltration of CINC-positive neutrophils, and a continuous CINC messenger RNA up-regulation and activation of NF-kB in the liver only in hepatectomized rats. These phenomena were all effectively prevented by pretreatment and posttreatment with a PAF receptor antagonist, TCV-309. Heptectomized rats showed NF-kB staining in hepatocytes, Kupffer cells, and neutrophils around necrosis 4 hours after the LPS injection, representing the activation of this factor in these cells.Conclusions. Based on these results, we propose that PAD contributes to continuous CINC up-regulation and NF-kB activation via accumulation and activation of neutrophils, and thereby is involved in LPS-induced liver injury in regenerating rat liver.