Singh Rajat, Czaja Mark J
Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
J Gastroenterol Hepatol. 2007 Jun;22 Suppl 1:S45-8. doi: 10.1111/j.1440-1746.2006.04646.x.
Oxidative stress has been implicated as the mechanism of hepatocyte injury from numerous agents. Although reactive oxygen species injure cells by the modification of critical cellular macromolecules, recent studies have demonstrated the mechanistic involvement of oxidant stress-induced alterations in signal transduction cascades. Studies in menadione-treated hepatocytes have demonstrated differential effects of mitogen-activated protein kinase activation on hepatocyte death from acute oxidative stress. Activation of the extracellular signal-regulated kinase pathway 1/2 (ERK1/2) confers hepatocyte resistance to death whereas sustained c-Jun N-terminal kinase (JNK)/c-Jun/AP-1 activation promotes apoptosis. Redundant protective signals such as the protein kinase C/protein kinase D pathways also downregulate the JNK/c-Jun/AP-1 cascade and provide resistance to cell death. Although ERK1/2 overactivation also acts as a protective response to chronic oxidative stress, enhanced activation of this kinase sensitizes hepatocytes to death from free fatty acids in this setting. The outcome from challenge with an oxidative stress, therefore, depends on the integration of a series of signaling cascades that both protect against and promote hepatocyte apoptosis.
氧化应激被认为是多种因素导致肝细胞损伤的机制。尽管活性氧通过修饰关键细胞大分子来损伤细胞，但最近的研究表明氧化应激诱导的信号转导级联改变也参与其中。对经甲萘醌处理的肝细胞的研究表明，丝裂原活化蛋白激酶激活对急性氧化应激导致的肝细胞死亡具有不同影响。细胞外信号调节激酶1/2（ERK1/2）途径的激活赋予肝细胞抗死亡能力，而持续的c-Jun氨基末端激酶（JNK）/c-Jun/AP-1激活则促进细胞凋亡。冗余的保护信号如蛋白激酶C/蛋白激酶D途径也会下调JNK/c-Jun/AP-1级联反应并提供抗细胞死亡能力。尽管ERK1/2过度激活也作为对慢性氧化应激的一种保护反应，但在这种情况下，该激酶的增强激活会使肝细胞对游离脂肪酸诱导的死亡敏感。因此，氧化应激挑战的结果取决于一系列既能防止又能促进肝细胞凋亡的信号级联的整合。
