Tumor necrosis factor α, but not Fas, mediates hepatocellular apoptosis in the murine ischemic liver
Tumor necrosis factor α, but not Fas, mediates hepatocellular apoptosis in the murine ischemic liver
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DOI：
10.1053/gast.2002.30304
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发表时间：
2002-01-01
期刊：
影响因子：
29.4
通讯作者：
Clavien, PA
中科院分区：
文献类型：
--
作者：
Rüdiger, HA;Clavien, PA
背景与目的：肝细胞凋亡是肝脏缺血性损伤的重要特征。本研究的目的是确定细胞外诱导凋亡的小鼠缺血性肝脏。研究方法：使用各种基因敲除小鼠（TNF-受体1 [TNF-R1]-/-、Fas[lpr]-/-和Fas配体[gld]-/-）和用TNF-α合成抑制剂喷替茶碱预处理的野生型小鼠评价肿瘤坏死因子（TNF）-α和Fas信号传导的参与。结果如下：与假手术动物相比，野生型小鼠和TNF-R1缺陷小鼠缺血和再灌注后TNF-α的表达增加。喷替福林阻止TNF-α表达的上调。抑制TNF-α导致血清天冬氨酸转氨酶水平显著降低，动物存活时间延长。细胞凋亡标志物（末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸缺口标记染色，细胞色素C释放和半胱天冬酶3活性）持续降低，阻断TNF-α后动物存活时间延长。与此相反，抑制Fas信号并没有改变组织损伤或细胞凋亡的参数，动物的生存率保持不变。结论：我们确定TNF-α是缺血性肝脏中凋亡细胞死亡的重要诱导剂。无法确定Fas的作用。这些发现可能会导致新的策略，以防止缺血性损伤的肝脏。
Background & Aims: Apoptosis of hepatocytes is a central feature of ischemic injury in the liver. The aim of this study was to identify extracellular inducers of apoptosis in the murine ischemic liver. Methods: Involvement of tumor necrosis factor (TNF)-alpha and Fas signaling was evaluated using various knockout mice (TNF-receptor 1 [TNF-R1]-/-, Fas[lpr]-/-, and Fas ligand[gld]-/-) and wild-type mice pretreated with pentoxifylline, an inhibitor of TNF-alpha synthesis. Results: Expression of TNF-alpha was increased after ischemia and reperfusion in wild-type mice and TNF-R1-deficient mice when compared with sham-operated animals. Pentoxifylline prevented up-regulation of TNF-alpha expression. Inhibition of TNF-alpha resulted in significant decrease of serum aspartate aminotransferase levels and prolonged animal survival. Markers of apoptosis (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nickend labeling staining, cytochrome C release, and caspase 3 activity) were consistently decreased, and animal survival was prolonged after blocking TNF-alpha. In contrast, Inhibition of Fas signaling did not alter parameters of tissue injury or apoptosis, and animal survival remained unchanged. Conclusions: We identify TNF-alpha as a crucial inducer of apoptotic cell death in the ischemic liver. A role for Fas could not be identified. These findings may lead to novel strategies to prevent ischemic injury of the liver.