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Oxidative stress stimulates proliferation and invasiveness of hepatic stellate cells via a MMP2-mediated mechanism.
Hepatology. 2005 May; 41(5):1074-84.Hep

Abstract

Experimental evidence indicates that reactive oxygen species (ROS) are involved in the development of hepatic fibrosis; they induce hepatic stellate cells (HSC) proliferation and collagen synthesis. To address the role of matrix metalloproteinase (MMP)-2 in promoting HSC proliferation during hepatic injury, we investigated whether oxidative stress modulates the growth and invasiveness of HSC by influencing MMP-2 activation. Cell invasiveness and proliferation, which were studied using Boyden chambers and by counting cells under a microscope, were evaluated after treatment with a superoxide-producing system, xanthine plus xanthine oxidase (X/XO), in the presence or absence of antioxidants and MMP inhibitors. Expression and activation of MMP-2 were evaluated via gel zymography, immunoassay, and ribonuclease protection assay. The addition of X/XO induced proliferation and invasiveness of human HSC in a dose-dependent manner. The addition of antioxidants as well as MMP-2-specific inhibitors impaired these phenomena. X/XO treatment increased MMP-2 expression and secretion appreciably and significantly induced members of its activation complex, specifically membrane-type 1 MMP and tissue inhibitor metalloproteinase 2. To study the intracellular signaling pathways involved in X/XO-induced MMP-2 expression, we evaluated the effects of different kinase inhibitors. The inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) and phosphatidyl inositol 3-kinase (PI3K) abrogated X/XO-elicited MMP-2 upregulation and completely prevented X/XO-induced growth and invasiveness of HSC. In conclusion, our findings suggest that MMP-2 is required for the mitogenic and proinvasive effects of ROS on HSC and demonstrate that ERK1/2 and PI3K are the main signals involved in ROS-mediated MMP-2 expression.

Authors+Show Affiliations

Gastroenterology Unit, Department of Clinical Pathophysiology, University of Florence, Florence, Italy. a.galli@dfc.unifi.itNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15841469

Citation

Galli, Andrea, et al. "Oxidative Stress Stimulates Proliferation and Invasiveness of Hepatic Stellate Cells Via a MMP2-mediated Mechanism." Hepatology (Baltimore, Md.), vol. 41, no. 5, 2005, pp. 1074-84.
Galli A, Svegliati-Baroni G, Ceni E, et al. Oxidative stress stimulates proliferation and invasiveness of hepatic stellate cells via a MMP2-mediated mechanism. Hepatology. 2005;41(5):1074-84.
Galli, A., Svegliati-Baroni, G., Ceni, E., Milani, S., Ridolfi, F., Salzano, R., Tarocchi, M., Grappone, C., Pellegrini, G., Benedetti, A., Surrenti, C., & Casini, A. (2005). Oxidative stress stimulates proliferation and invasiveness of hepatic stellate cells via a MMP2-mediated mechanism. Hepatology (Baltimore, Md.), 41(5), 1074-84.
Galli A, et al. Oxidative Stress Stimulates Proliferation and Invasiveness of Hepatic Stellate Cells Via a MMP2-mediated Mechanism. Hepatology. 2005;41(5):1074-84. PubMed PMID: 15841469.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Oxidative stress stimulates proliferation and invasiveness of hepatic stellate cells via a MMP2-mediated mechanism. AU - Galli,Andrea, AU - Svegliati-Baroni,Gianluca, AU - Ceni,Elisabetta, AU - Milani,Stefano, AU - Ridolfi,Francesco, AU - Salzano,Renata, AU - Tarocchi,Mirko, AU - Grappone,Cecilia, AU - Pellegrini,Giulia, AU - Benedetti,Antonio, AU - Surrenti,Calogero, AU - Casini,Alessandro, PY - 2005/4/21/pubmed PY - 2005/6/2/medline PY - 2005/4/21/entrez SP - 1074 EP - 84 JF - Hepatology (Baltimore, Md.) JO - Hepatology VL - 41 IS - 5 N2 - Experimental evidence indicates that reactive oxygen species (ROS) are involved in the development of hepatic fibrosis; they induce hepatic stellate cells (HSC) proliferation and collagen synthesis. To address the role of matrix metalloproteinase (MMP)-2 in promoting HSC proliferation during hepatic injury, we investigated whether oxidative stress modulates the growth and invasiveness of HSC by influencing MMP-2 activation. Cell invasiveness and proliferation, which were studied using Boyden chambers and by counting cells under a microscope, were evaluated after treatment with a superoxide-producing system, xanthine plus xanthine oxidase (X/XO), in the presence or absence of antioxidants and MMP inhibitors. Expression and activation of MMP-2 were evaluated via gel zymography, immunoassay, and ribonuclease protection assay. The addition of X/XO induced proliferation and invasiveness of human HSC in a dose-dependent manner. The addition of antioxidants as well as MMP-2-specific inhibitors impaired these phenomena. X/XO treatment increased MMP-2 expression and secretion appreciably and significantly induced members of its activation complex, specifically membrane-type 1 MMP and tissue inhibitor metalloproteinase 2. To study the intracellular signaling pathways involved in X/XO-induced MMP-2 expression, we evaluated the effects of different kinase inhibitors. The inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) and phosphatidyl inositol 3-kinase (PI3K) abrogated X/XO-elicited MMP-2 upregulation and completely prevented X/XO-induced growth and invasiveness of HSC. In conclusion, our findings suggest that MMP-2 is required for the mitogenic and proinvasive effects of ROS on HSC and demonstrate that ERK1/2 and PI3K are the main signals involved in ROS-mediated MMP-2 expression. SN - 0270-9139 UR - https://www.unboundmedicine.com/medline/citation/15841469/Oxidative_stress_stimulates_proliferation_and_invasiveness_of_hepatic_stellate_cells_via_a_MMP2_mediated_mechanism_ L2 - https://doi.org/10.1002/hep.20683 DB - PRIME DP - Unbound Medicine ER -