The study of mechanism of liver cell injury induce by edotoxin shock and ischemia, and its clinical application

Lazaroid（21-氨基类固醇）是一种非糖皮质激素类固醇，其合成是为了抑制脂质过氧化而不含糖皮质激素活性。本研究旨在确定lazaroid是否可以通过抑制Kupffer细胞的核因子- kb （NF-kB）激活来抑制促炎基因的上调。通过降低肝脏脂质过氧化、TNF-α、肝酶释放和中性粒细胞浸润，类Lazaroid处理显著提高了LPS注射后48小时的存活率，并对LPS诱导的肝损伤具有保护作用。类Lararoid对肝脏NF-kB活化也有抑制作用。在Kupffer细胞实验中，lazaroid处理以剂量依赖性方式抑制TNF-α的释放。Lazaroid还抑制了LPS添加后1 h和30 min Kupffer细胞TNF mRNA表达和NF-kB活化的增加。此外，lazaroid处理抑制了lps刺激的Kupffer细胞中IkB蛋白的降解。这些结果表明，lazaroid可以通过抑制Kupffer细胞NF-kB活化来抑制促炎基因的上调，是一种治疗内毒素休克的有前景的新药。

Lazaroid (21-aminosteroid) is a nonglucocorticoid steroid that was synthesized to inhibit lipid peroxidation without the glucocorticoid activity. The present study was undertaken to determine whether lazaroid could suppress pro-inflammatory gene up-regulation through inhibition of nuclear factor-kB (NF-kB) activation in Kupffer cells.Lazaroid treatment significantly increased survival rates 48 hours after LPS injection and protected against LPS-induced liver injury in vivo, as indicated by the decreased hepatic lipid peroxidation, TNF-α, hepatic enzyme release, and neutrophil infiltration in the liver. Lararoid also showed inhibitory effects on NF-kB activation in the liver. In the experiment of Kupffer cells, lazaroid treatment suppressed the release of TNF-α in a dose dependent manner. Lazaroid also inhibited the increase of TNF mRNA expression and NF-kB activation in Kupffer cells 1 h and 30 min, respectively, after LPS addition. Furthermore, lazaroid treatment suppressed the degradation of IkB proteins in LPS-stimulated Kupffer cells.These results suggest that lazaroid can suppress proinflammatory gene up-regulation through inhibition of NF-kB activation in Kupffer cells and that this is a promising new drug for the treatment of endotoxin shock.