Dose dependent and divergent effects of superoxide anion on cell death, proliferation, and migration of activated human hepatic stellate cells. Issue 1 (24th July 2005)

• Record Type: Journal Article
• Authors: Novo, E; Marra, F; Zamara, E; Valfrè di Bonzo, L; Caligiuri, A; Cannito, S; Antonaci, C; Colombatto, S; Pinzani, M; Parola, M
• Is Part Of: Gut. Volume 55:Issue 1(2006)
• Page Start: 90
• Page End: 97
• Publication Date: 2005-07-24
• Subjects: CLDs, chronic liver diseases -- ECM, extracellular matrix -- MFs, myofibroblast-like cells -- HSC, hepatic stellate cells -- HSC/MFs, activated hepatic stellate cells in myofibroblast-like phenotype -- ROI, reactive oxygen intermediates -- O2−, superoxide anion -- H2O2, hydrogen peroxide -- HNE, 4-hydroxynonenal -- TIMP, tissue inhibitor of metalloproteinases -- PDGF, platelet derived growth factor -- TGF-β1, transforming growth factor β1 -- ECL, enhanced chemiluminescence -- SFI medium, serum free Iscove's medium -- NO, nitric oxide -- L-NAME, Nω-nitro-L-arginine methyl ester -- LDH, lactate dehydrogenase -- X/XO, hypoxanthine/xanthine oxidase system generating superoxide anion -- SOD, superoxide dismutase -- ERK, extracellular regulated kinase -- PI-3 K, phosphatidyl inositol 3-kinase; activated human hepatic stellate cells -- liver fibrosis -- superoxide anion -- myofibroblast migration -- induction of cell death; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gut.2005.069633
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : 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 (H2 O2 ), 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 H2 O2 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 H2 O2 did not affect Ras/ERK or proliferative response. A high rate of O2 − generation or elevated levels of H2 O2 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.