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

Lazaroid（21-aminosteroid）是一种非糖皮质激素类固醇，其被合成以抑制脂质过氧化，而不具有糖皮质激素活性。本研究旨在探讨Lazaroid是否能通过抑制Kupffer细胞核因子-kB（NF-kB）的活化来抑制促炎基因的上调。Lazaroid治疗可显著提高LPS注射后48小时的存活率，并通过减少肝脏脂质过氧化、TNF-α、肝酶释放、和中性粒细胞浸润Lararoid还显示出对肝脏中NF-κ B活化的抑制作用。Kupffer细胞实验中，Lazaroid处理抑制TNF-α的释放，并呈剂量依赖性。Lazaroid还抑制LPS加入后1h和30 min Kupffer细胞TNF mRNA表达和NF-κ B活化的增加。lazaroid可抑制LPS刺激的Kupffer细胞中IkB蛋白的降解，提示lazaroid可通过抑制Kupffer细胞中NF-κ B的活化来抑制促炎基因的上调，是一种很有前途的治疗内毒素休克的新药。

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.