Oxidant stress-induced liver injury in vivo: role of apoptosis, oncotic necrosis, and c-Jun NH2-terminal kinase activation
Oxidant stress-induced liver injury in vivo: role of apoptosis, oncotic necrosis, and c-Jun NH2-terminal kinase activation
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DOI：
10.1152/ajpgi.90435.2008
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发表时间：
2009-03-01
影响因子：
4.5
通讯作者：
Jaeschke, Hartmut
中科院分区：
文献类型：
--
作者：
Hong, Ji-Young;Lebofsky, Margitta;Jaeschke, Hartmut
洪建勇，李建军，李建军，等。氧化应激诱导的肝损伤：细胞凋亡、肿瘤坏死和c-Jun nh2末端激酶的激活。[J] .中国生物医学工程学报，2009。首次发表于2009年1月8日；doi: 10.1152 / ajpgi.90435.2008。氧化应激在多种肝脏疾病中起关键作用。在培养的肝细胞中，超氧化物的形成导致c-Jun nh2末端激酶（JNK）和caspase依赖性的凋亡。为了在体内验证这些发现，雄性Fisher大鼠用地奎特和甲萘醌治疗。通过增加谷胱甘肽二硫和4-羟基壬烯醛蛋白加合物的形成，证实了这两种化合物引起的氧化应激。血浆丙氨酸转氨酶活性从对照组的46 +/- 4 U/l增加到diquat处理6 h后的955 +/- 90 U/l。苏木精和伊红染色显示肝脏切片在3和6小时时出现大面积坏死细胞。DNA链断裂，用末端脱氧核苷酸转移酶介导的dUTP镍端标记（TUNEL）试验评估，显示TUNEL阳性细胞簇，其中染色主要是细胞质，细胞肿胀，表明肿瘤坏死。在diquat处理后的0 - 6小时内，caspase-3活性和DNA片段释放到细胞质中的量均无显著增加。尽管高剂量diquat激活了JNK，但JNK抑制剂SP-600125对diquat诱导的坏死没有保护作用。美那酮单独不引起肝损伤，但与福尔酮和FeSO4联合可引起中度肿瘤性坏死。另一方面，以半乳糖胺/内毒素作为凋亡阳性对照，caspase-3活性增加259%，tunel阳性细胞凋亡形态增加103倍，DNA片段化增加6倍。数据表明，体内由diquat诱导的超氧化物形成引发的肝细胞死亡主要由肿瘤坏死介导，与JNK激活无关。
Hong JY, Lebofsky M, Farhood A, Jaeschke H. Oxidant stress-induced liver injury in vivo: role of apoptosis, oncotic necrosis, and c-Jun NH2-terminal kinase activation. Am J Physiol Gastrointest Liver Physiol 296: G572-G581, 2009. First published January 8, 2009; doi:10.1152/ajpgi.90435.2008.-Oxidant stress is critically involved in various liver diseases. Superoxide formation causes c-Jun NH2-terminal kinase (JNK)- and caspase-dependent apoptosis in cultured hepatocytes. To verify these findings in vivo, male Fisher rats were treated with diquat and menadione. The oxidant stress induced by both compounds was confirmed by increased formation of glutathione disulfide and 4-hydroxynonenal protein adducts. Plasma alanine aminotransferase activities increased from 46 +/- 4 U/l in controls to 955 +/- 90 U/l at 6 h after diquat treatment. Hematoxylin and eosin staining of liver sections revealed large areas of necrotic cells at 3 and 6 h. DNA strandbreaks, evaluated with the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, showed clusters of TUNEL-positive cells, where the staining was predominantly cytosolic and the cells were swollen, indicating oncotic necrosis. There was no significant increase in caspase-3 activities or relevant release of DNA fragments into the cytosol at any time between 0 and 6 h after diquat treatment. Despite the activation of JNK after high doses of diquat, the JNK inhibitor SP-600125 did not protect against diquat-induced necrosis. Menadione alone did not cause liver injury, but, in combination with phorone and FeSO4, induced moderate oncotic necrosis. On the other hand, if animals were treated with galactosamine/endotoxin as positive control for apoptosis, caspase-3 activities were increased by 259%, the number of TUNEL-positive cells with apoptotic morphology was increased 103-fold, and DNA fragmentation was enhanced 6-fold. The data indicate that liver cell death initiated by diquat-induced superoxide formation in vivo is mediated predominantly by oncotic necrosis and is independent of JNK activation.