期刊
LIVER INTERNATIONAL
卷 29, 期 6, 页码 922-932出版社
WILEY
DOI: 10.1111/j.1478-3231.2009.02004.x
关键词
cell death; glutathione; proliferation; reactive oxygen species; signal transduction; stellate cells
资金
- Dutch Digestive Foundation
- J. K. de Cock Foundation
In chronic liver injury, hepatic stellate cells (HSCs) proliferate and produce excessive amounts of connective tissue causing liver fibrosis and cirrhosis. Oxidative stress has been implicated as a driving force of HSC activation and proliferation, although contradictory results have been described. To determine the effects of oxidative stress on activated HSC proliferation, survival and signalling pathways. Serum-starved culture-activated rat HSCs were exposed to the superoxide anion donor menadione (5-25 mu mol/L) or hydrogen peroxide (0.2-5 mmol/L). Haem oxygenase-1 mRNA expression, glutathione status, cell death, phosphorylation of mitogen-activated protein (MAP) kinases and proliferation were investigated. Menadione induced apoptosis in a dose- and time-dependent, but caspase-independent manner. Hydrogen peroxide induced necrosis only at extremely high concentrations. Both menadione and hydrogen peroxide activated Jun N-terminal kinase (JNK) and p38. Hydrogen peroxide also activated extracellular signal-regulated protein. Menadione, but not hydrogen peroxide, reduced cellular glutathione levels. Inhibition of JNK or supplementation of glutathione reduced menadione-induced apoptosis. Non-toxic concentrations of menadione or hydrogen peroxide inhibited platelet-derived growth factor- or/and serum-induced proliferation. Reactive oxygen species (ROS) inhibit HSC proliferation and promote HSC cell death in vitro. Different ROS induce different modes of cell death. Superoxide anion-induced HSC apoptosis is dependent on JNK activation and glutathione status.
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