An inhibitor of c-Jun NH2-terminal kinase, SP600125, protects mice from D-galactosamine/lipopolysaccharide-induced hepatic failure by modulating BH3-only proteins
An inhibitor of c-Jun NH2-terminal kinase, SP600125, protects mice from D-galactosamine/lipopolysaccharide-induced hepatic failure by modulating BH3-only proteins
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DOI：
10.1016/j.lfs.2006.12.034
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发表时间：
2007-03-13
期刊：
影响因子：
6.1
通讯作者：
Aoyagi, Yutaka
中科院分区：
文献类型：
--
作者：
Takamura, Masaaki;Matsuda, Yasunobu;Aoyagi, Yutaka
暴发性肝功能衰竭（FHF）是一种严重的临床综合征，其特征是大量肝细胞凋亡和极高的死亡率。c-Jun-N-末端激酶（JNK）途径是由几种形式的肝损伤激活的重要的应激反应性激酶。本研究的目的是评估JNK在D-半乳糖胺（GalN）/脂多糖（LPS）诱导的肝损伤中的作用，FHF的实验模型，使用SP 600125。小分子JNK特异性抑制剂。给小鼠腹膜内剂量的GalN（800 μ g/g体重）/LPS（100 ng/g体重），同时进行和不进行皮下SP 600125（50 mg/kg体重）处理（在GalN/LPS施用前6和2小时以及在GalN/LPS施用后2小时）。GalN/LPS处理诱导持续的INK激活。SP 600125的给药降低了INK活性，抑制了死亡率和血清丙氨酸转氨酶和天冬氨酸转氨酶的升高，但对血清肿瘤坏死因子-α没有影响。并减少GalN/LPS给药后的肝细胞凋亡。为了支持JNK在促进细胞凋亡途径中的作用，SP 600125阻止了细胞色素c的释放、caspase-9和caspase-3的活性。此外，SP 600125在注射GalN/LPS后的早期下调Bad的mRNA和蛋白表达，并在后期阻止Bid切割。这些结果证实了JNK在GalN/LPS诱导的FHF中作为关键凋亡介质的作用。SP 600125具有通过下调Bad和抑制Bid裂解来保护FTF的潜力。(c)2007年爱思唯尔公司All rights reserved.
Fulminant hepatic failure (FHF) is a dramatic clinical syndrome characterized by massive hepatocyte apoptosis and very high mortality. The c-Jun-N-terminal kinase (JNK) pathway is an important stress-responsive kinase activated by several forms of liver injury. The aim of this study is to assess the role of JNK during D-galactosamine (GalN)/lipopolysaccharide (LPS)-induced liver injury, an experimental model of FHF, using SP600125. a small molecule JNK-specific inhibitor. Mice were given an intraperitoneal dose of GalN (800 mu g/g body weight)/LPS (100 ng/g body weight) with and without subcutaneous SP600125 (50 mg/kg body weight) treatment (at 6 and 2 h before and 2 h after GalN/LPS administration). GalN/LPS treatment induced sustained INK activation. Administration of SP600125 diminished INK activity, suppressed lethality and the elevation of both serum alanine aminotransferase and aspartate aminotransferase, but had no effect on serum tumor necrosis factor-alpha. and reduced hepatocyte apoptosis after GalN/LPS administration. In support of the role of JNK in promoting the mitochondria-mediated apoptosis pathway, SP600125 prevented cytochrome c release, caspase-9 and caspase-3 activity. Moreover, SP600125 downregulated the mRNA and protein expression of Bad in the early periods following GalN/LPS injection and prevented Bid cleavage in the late periods. These results confirm the role of JNK as a critical apoptotic mediator in GalN/LPS-induced FHF. SP600125 has the potential to protect FTF by downregulating Bad and inhibiting Bid cleavage. (c) 2007 Elsevier Inc. All rights reserved.