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Oxidative stress stimulates proliferation and invasiveness of hepatic stellate cells via a MMP2‐mediated mechanism
Author(s) -
Galli Andrea,
SvegliatiBaroni Gianluca,
Ceni Elisabetta,
Milani Stefano,
Ridolfi Francesco,
Salzano Renata,
Tarocchi Mirko,
Grappone Cecilia,
Pellegrini Giulia,
Benedetti Antonio,
Surrenti Calogero,
Casini Alessandro
Publication year - 2005
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.20683
Subject(s) - hepatic stellate cell , oxidative stress , reactive oxygen species , microbiology and biotechnology , matrix metalloproteinase , protein kinase b , xanthine oxidase , cell growth , signal transduction , biology , pi3k/akt/mtor pathway , downregulation and upregulation , nadph oxidase , chemistry , biochemistry , endocrinology , enzyme , gene
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. (H EPATOLOGY 2005;41:1074–1084.)