Miyoshi H, Rust C, Roberts P J, Burgart L J, Gores G J
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.
Gastroenterology. 1999 Sep;117(3):669-77. doi: 10.1016/s0016-5085(99)70461-0.
BACKGROUND & AIMS: Cholestatic liver injury results from the intrahepatic accumulation of toxic bile salts. Toxic bile salt-induced hepatocyte apoptosis in vitro is Fas dependent. The aim of this study was to ascertain if hepatocyte apoptosis in vivo during cholestasis is Fas dependent.
Studies were performed in bile duct-ligated (BDL) Fas-deficient lpr (lymphoproliferation) and wild-type mice.
Hepatocyte apoptosis was the predominant mechanism of cell death as determined by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling and trypan blue assays to quantitate apoptosis and necrosis. The mechanisms of hepatocyte apoptosis were dependent on the presence or absence of the Fas receptor and the duration of BDL. After BDL of 3 days' duration, increased hepatocyte apoptosis occurred only in wild-type but not lpr mice, indicating the apoptosis was Fas dependent. In contrast, after BDL of >/=7 days, hepatocyte apoptosis also occurred in lpr animals consistent with a Fas-independent mechanism of apoptosis. Hepatocyte apoptosis in BDL lpr mice was associated with an increase in Bax expression and Bax association with mitochondria.
During extrahepatic cholestasis, hepatocyte apoptosis is mediated by Fas. However, in the absence of the Fas receptor, additional mechanisms of hepatocyte apoptosis occur. Inhibition of multiple apoptotic pathways is necessary to attenuate chronic cholestatic liver injury.
胆汁淤积性肝损伤是由有毒胆盐在肝内蓄积所致。有毒胆盐在体外诱导的肝细胞凋亡是Fas依赖性的。本研究旨在确定胆汁淤积期间体内肝细胞凋亡是否为Fas依赖性。
在胆管结扎（BDL）的Fas缺陷型lpr（淋巴细胞增殖）小鼠和野生型小鼠中进行研究。
通过末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸缺口末端标记法和台盼蓝试验来定量凋亡和坏死，结果表明肝细胞凋亡是细胞死亡的主要机制。肝细胞凋亡机制取决于Fas受体的有无以及BDL的持续时间。BDL 3天后，仅野生型小鼠肝细胞凋亡增加，而lpr小鼠未增加，表明凋亡是Fas依赖性的。相反，BDL≥7天后，lpr动物也出现肝细胞凋亡，这与Fas非依赖性凋亡机制一致。BDL lpr小鼠的肝细胞凋亡与Bax表达增加以及Bax与线粒体的结合有关。
在肝外胆汁淤积期间，肝细胞凋亡由Fas介导。然而，在缺乏Fas受体时，会出现肝细胞凋亡的其他机制。抑制多种凋亡途径对于减轻慢性胆汁淤积性肝损伤是必要的。
