HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS REGISTER		Author Keyword(s) Vol Page [Advanced]

This Article Full Text Full Text (PDF) All Versions of this Article: gut.2005.069633v1 55/1/90    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this link to a friend Similar articles in this journal Similar articles in PubMed Add article to my folders Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Novo, E Articles by Parola, M Search for Related Content PubMed PubMed Citation Articles by Novo, E Articles by Parola, M

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

¹ Dip Medicina e Oncologia Sperimentale, University of Torino, Torino, Italy
² Dip Medicina Interna-Centro di Ricerca, Trasferimento e Alta Formazione "DENOTHE", University of Florence, Florence, Italy

Correspondence to:
Correspondence to:
Professor M Parola
Università degli Studi di Torino, Dip Medicina e Oncologia Sperimentale, C so Raffaello 30, 10125 Torino, Italy; maurizio.parola{at}unito.it

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.

Abbreviations: 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-ß1, transforming growth factor ß1; ECL, enhanced chemiluminescence; SFI medium, serum free Iscove’s medium; NO, nitric oxide; L-NAME, N-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

Keywords: activated human hepatic stellate cells; liver fibrosis; superoxide anion; myofibroblast migration; induction of cell death

This article has been cited by other articles:

				H. Rehman, V. K. Ramshesh, T. P. Theruvath, I. Kim, R. T. Currin, S. Giri, J. J. Lemasters, and Z. Zhong NIM811 (N-Methyl-4-isoleucine Cyclosporine), a Mitochondrial Permeability Transition Inhibitor, Attenuates Cholestatic Liver Injury but Not Fibrosis in Mice J. Pharmacol. Exp. Ther., December 1, 2008; 327(3): 699 - 706. [Abstract] [Full Text] [PDF]

				S. Cannito, E. Novo, A. Compagnone, L. Valfre di Bonzo, C. Busletta, E. Zamara, C. Paternostro, D. Povero, A. Bandino, F. Bozzo, et al. Redox mechanisms switch on hypoxia-dependent epithelial-mesenchymal transition in cancer cells Carcinogenesis, December 1, 2008; 29(12): 2267 - 2278. [Abstract] [Full Text] [PDF]

				L V. di Bonzo, I Ferrero, C Cravanzola, K Mareschi, D Rustichell, E Novo, F Sanavio, S Cannito, E Zamara, M Bertero, et al. Human mesenchymal stem cells as a two-edged sword in hepatic regenerative medicine: engraftment and hepatocyte differentiation versus profibrogenic potential Gut, February 1, 2008; 57(2): 223 - 231. [Abstract] [Full Text] [PDF]

				S. L. Friedman Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver Physiol Rev, January 1, 2008; 88(1): 125 - 172. [Abstract] [Full Text] [PDF]

				E. Novo, S. Cannito, E. Zamara, L. V. di Bonzo, A. Caligiuri, C. Cravanzola, A. Compagnone, S. Colombatto, F. Marra, M. Pinzani, et al. Proangiogenic Cytokines as Hypoxia-Dependent Factors Stimulating Migration of Human Hepatic Stellate Cells Am. J. Pathol., June 1, 2007; 170(6): 1942 - 1953. [Abstract] [Full Text] [PDF]