Dose dependent and divergent effects of superoxide anion on cell death, proliferation, and migration of activated human hepatic stellate cells
| Autor: | Stefania Cannito, Massimo Pinzani, Maurizio Parola, Sebastiano Colombatto, E. Zamara, L. Valfrè di Bonzo, Erica Novo, Alessandra Caligiuri, Fabio Marra, C Antonaci |
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| Jazyk: | angličtina |
| Rok vydání: | 2006 |
| Předmět: |
MAPK/ERK pathway
Programmed cell death Liver cytology Apoptosis Collagen Type I chemistry.chemical_compound Cell Movement Superoxides Humans Extracellular Signal-Regulated MAP Kinases Cells Cultured Cell Proliferation biology Cell Death Dose-Response Relationship Drug Superoxide Cell growth Gastroenterology Hydrogen Peroxide Cell biology chemistry Liver Hepatic stellate cell biology.protein Hepatocytes Platelet-derived growth factor receptor Signal Transduction |
| Popis: | 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 (O 2 •− ) and, for comparison, hydrogen peroxide (H 2 O 2 ), were analysed in terms of cytotoxicity, proliferative response, and migration. Methods: Cultured human HSC/MFs were exposed to controlled O 2 •− generation by hypoxanthine/xanthine oxidase systems or to a range of H 2 O 2 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 O 2 •− and only high rates of O 2 •− generation induced either necrotic or apoptotic cell death. Non-cytotoxic low levels of O 2 •− , 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 H 2 O 2 did not affect Ras/ERK or proliferative response. A high rate of O 2 •− generation or elevated levels of H 2 O 2 induced cytoskeletal alterations, block in motility, and inhibition of PDGF dependent DNA synthesis. Conclusions: Low non-cytotoxic levels of extracellularly generated O 2 •− may stimulate selected profibrogenic responses in human HSC/MFs without affecting proliferation. |
| Databáze: | OpenAIRE |
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