INDUCTION OF APOPTOSIS IN THE MURINE LIVER WITH RECOMBINANT HUMAN ACTIVIN-A
INDUCTION OF APOPTOSIS IN THE MURINE LIVER WITH RECOMBINANT HUMAN ACTIVIN-A
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DOI：
10.1002/hep.1840200413
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发表时间：
1994-10-01
期刊：
影响因子：
13.5
通讯作者：
GILLETT, NA
中科院分区：
文献类型：
--
作者：
HULLY, JR;CHANG, L;GILLETT, NA
重组人激活素A是转化生长因子-β超家族的一员，在啮齿动物肝脏和原代肝细胞培养物中诱导显著的细胞损失。从组织学和生物化学上讲，肝细胞死亡是由细胞凋亡介导的，细胞凋亡是一种程序性细胞死亡。通过皮下植入的微型泵，用200或500 μ g重组人激活素A/kg体重/天治疗雄性小鼠长达3天。取肝脏进行光学和电子显微镜检查、DNA分离和原位缺口末端标记。用10 ng/ml重组人激活素A处理大鼠肝细胞的原代培养物24 h，然后收获用于电子显微镜检查和DNA分离。由于中央静脉周围肝细胞的萎缩和死亡，输注激活素A引起剂量依赖性肝脏质量损失。在形态学上，垂死的细胞表现出凋亡的所有特征性核和细胞质特征。经激活素A处理的完整肝脏和原代培养物中分离的低分子量DNA表现出典型的寡聚体梯状结构。缺口末端标记的DNA原位证实，几乎所有的地形凋亡肝细胞的DNA片段。目前接受的细胞凋亡标准（即，特异性形态学改变和DNA的核小体间剪切）在体外和体内激活素A处理的肝细胞中是明显的，从而得出细胞损失主要通过凋亡发生的结论。这些观察结果表明，激活素A可能是重要的肝脏稳态。
Recombinant human activin A, a member of the transforming growth factor-p superfamily, induced significant cell loss in rodent livers and in primary hepatocyte cultures. Histologically and biochemically the hepatocyte death was mediated by apoptosis, a form of programmed cell death. Male mice were treated with 200 or 500 mu g recombinant human activin A/kg body wt/day for up to 3 days by means of a subcutaneously implanted minipump. Livers were taken for light and electron microscopy, DNA isolation and in situ nick end-labeling. Primary cultures of rat hepatocytes were treated with 10 ng/ml recombinant human activin A for 24 hr before being harvested for electron microscopy and DNA isolation. Infusion of activin A evoked dose-dependent loss of liver mass due to the atrophy and death of hepatocytes around the central vein. Morphologically, the dying cells demonstrated all the characteristic nuclear and cytoplasmic features of apoptosis. Low molecular weight DNA isolated activin A-treated intact livers and primary cultures exhibited the typical oligosomal ladder. Nick end-labeling of DNA in situ confirmed that virtually all topographical apoptotic hepatocytes had fragmented DNA. The currently accepted criteria for apoptosis (i.e., specific morphological alterations and internucleosomal clipping of DNA) were evident in activin A-treated hepatocytes both in vitro and in vivo,leading to the conclusion that cell loss occurs mainly through apoptosis. These observations suggest that activin A may be important in hepatic homeostasis.