Dose dependent and divergent effects of superoxide anion on cell death, proliferation, and migration of activated human hepatic stellate cells

Novo, E.; Marra, F.; Zamara, E.; di Bonzo, L. Valfrè; Caligiuri, A.; Cannito, S.; Antonaci, C.; Colombatto, S.; Pinzani, M.; Parola, M.
January 2006
Gut;Jan2006, Vol. 55 Issue 1, p90
Academic Journal
Background and aim: Activated myofibroblast-like cells, originating from hepatic stellate cells (HSC/MFs) or other cellular sources, play a key profibrogenic role in chronic liver diseases (CLDs) that, as suggested by studies in animal models or rat HSC/MFs, may be modulated by reactive oxygen intermediates (ROI). In this study, human HSC/MFs, exposed to different levels of superoxide anion (O2...) and, for comparison, hydrogen peroxide (H2O2), were analysed in terms of cytotoxicity, proliferative response, and migration. Methods: Cultured human HSC/MFs were exposed to controlled O2... generation by hypoxanthine/xanthine oxidase systems or to a range of H2O2 concentrations. Induction of cell death, proliferation, and migration were investigated using morphology, molecular biology, and biochemical techniques. Results: Human HSC/MFs were shown to be extremely resistant to induction of cell death by O2... and only high rates of O2... generation induced either necrotic or apoptotic cell death. Non-cytotoxic low levels of O2..., able to upregulate procollagen type I expression (but not tissue inhibitor of metalloproteinase 1 and 2), stimulated migration of human HSC/MFs in a Ras/extracellular regulated kinase (ERK) dependent, antioxidant sensitive way, without affecting basal or platelet derived growth factor (PDGF) stimulated cell proliferation. Non-cytotoxic levels of H2O2 did not affect Ras/ERK or proliferative response. A high rate of O2... generation or elevated levels of H2O2 induced cytoskeletal alterations, block in motility, and inhibition of PDGF dependent DNA synthesis. Conclusions: Low non-cytotoxic levels of extracellularly generated O2... may stimulate selected profibrogenic responses in human HSC/MFs without affecting proliferation.


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