Apoptosis and necrosis after warm ischemia-reperfusion injury of the pig liver and their inhibition by ONO-1714
作者:
Makoto Meguro,
Tadashi Katsuramaki,
Hitoshi Kimura,
Masato Isobe,
Minoru Nagayama,
Kazuma Kukita,
Akihiro Nui,
Koichi Hirata,
期刊:
Transplantation
(OVID Available online 2003)
卷期:
Volume 75,
issue 5
页码: 703-710
ISSN:0041-1337
年代: 2003
出版商: OVID
数据来源: OVID
摘要:
Background.It is still controversial whether a major mode of cell death during hepatic ischemia-reperfusion (I/R) injuries is apoptosis or necrosis. Moreover, the correlation between these cell deaths and the effects of a novel inducible nitric oxide synthase inhibitor (ONO-1714) has not been studied before.Methods.Pigs were subjected to 180 min of hepatic warm I/R under extracorporeal circulation. The control group was not administered ONO-1714. In the ONO-1714 group, ONO-1714 was administered 5 min before ischemia at a dose of 0.05 mg/kg through a portal vein catheter. The apoptotic and necrotic changes after reperfusion were examined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and hematoxylin-eosin staining. Nitrotyrosine, active caspase-3, and cytochrome c were examined by immunohistochemistry. The plasma NO2-+ NO3-, aspartate aminotransferase, and lactate dehydrogenase levels were also examined.Results.In the control group, the frequency of apoptotic cells was only 2.6%; nevertheless, that of necrotic cells was 37% at 24 hr after reperfusion. ONO-1714 significantly attenuated apoptosis and necrosis, the expression of nitrotyrosine, and the increases of the plasma aspartate aminotransferase, lactate dehydrogenase, and NO2-+ NO3-levels in the reperfusion phase.Conclusions.A major mode of cell death during hepatic warm I/R injury was necrosis, and apoptosis was not dominant. These necrotic changes were caused by the excess production of peroxynitrite, and ONO-1714 greatly attenuated I/R injuries as the result of inhibition of the peroxynitrite production.
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