Wright M C, Issa R, Smart D E, Trim N, Murray G I, Primrose J N, Arthur M J, Iredale J P, Mann D A
Department of Molecular and Cell Biology, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, Scotland.
Gastroenterology. 2001 Sep;121(3):685-98. doi: 10.1053/gast.2001.27188.
BACKGROUND & AIMS: Hepatic stellate cells (HSCs) play a pivotal role in liver fibrosis and stimulating their apoptosis could be an effective treatment for liver fibrosis.
Activated HSCs, hepatocytes, and rats with liver fibrosis were treated with gliotoxin.
Addition of gliotoxin to activated (alpha-smooth muscle actin positive) rat and human HSCs resulted in morphologic alterations typical of apoptosis. Within 2-3 hours of incubation, caspase 3 activity was markedly induced and caspase inhibitor 1 (Z-VAD-FMK)-sensitive oligonucleosome-length DNA fragments were detectable by gel electrophoresis of low molecular weight DNA. Apoptosis was widespread as judged by fluorescence-activated cell sorter analysis and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining in both rat and human HSCs at concentrations that had no effect on the viability of rat hepatocytes. Gliotoxin treatment significantly reduced the number of activated stellate cells and mean thickness of bridging fibrotic septae in livers from rats treated with carbon tetrachloride.
These data demonstrate proof-of-concept that by up-regulating HSC apoptosis, the extent of fibrosis can be decreased in inflammatory liver injury.
肝星状细胞（HSCs）在肝纤维化过程中起关键作用，促使其凋亡可能是治疗肝纤维化的有效方法。
用胶质毒素处理活化的肝星状细胞、肝细胞以及肝纤维化大鼠。
将胶质毒素添加到活化的（α - 平滑肌肌动蛋白阳性）大鼠和人肝星状细胞中，会导致典型的凋亡形态学改变。孵育2 - 3小时内，半胱天冬酶3活性显著诱导，通过低分子量DNA凝胶电泳可检测到半胱天冬酶抑制剂1（Z - VAD - FMK）敏感的寡核苷酸长度DNA片段。通过荧光激活细胞分选分析和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染色判断，在对大鼠肝细胞活力无影响的浓度下，大鼠和人肝星状细胞中凋亡广泛存在。胶质毒素处理显著减少了四氯化碳处理大鼠肝脏中活化星状细胞的数量和桥接纤维化间隔的平均厚度。
这些数据证明了通过上调肝星状细胞凋亡来降低炎症性肝损伤中纤维化程度的概念验证。
