Document Detail


Oxidative stress stimulates proliferation and invasiveness of hepatic stellate cells via a MMP2-mediated mechanism.
MedLine Citation:
PMID:  15841469     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Andrea Galli; Gianluca Svegliati-Baroni; Elisabetta Ceni; Stefano Milani; Francesco Ridolfi; Renata Salzano; Mirko Tarocchi; Cecilia Grappone; Giulia Pellegrini; Antonio Benedetti; Calogero Surrenti; Alessandro Casini
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Hepatology (Baltimore, Md.)     Volume:  41     ISSN:  0270-9139     ISO Abbreviation:  Hepatology     Publication Date:  2005 May 
Date Detail:
Created Date:  2005-04-25     Completed Date:  2005-06-01     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  8302946     Medline TA:  Hepatology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1074-84     Citation Subset:  IM    
Affiliation:
Gastroenterology Unit, Department of Clinical Pathophysiology, University of Florence, Florence, Italy. a.galli@dfc.unifi.it
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MeSH Terms
Descriptor/Qualifier:
Cell Division / drug effects,  physiology
Cells, Cultured
Hepatocytes / cytology*,  enzymology*
Humans
Liver Cirrhosis / metabolism,  pathology
Matrix Metalloproteinase 2 / metabolism*
Matrix Metalloproteinases, Membrane-Associated
Metalloendopeptidases / metabolism
Mitogen-Activated Protein Kinase 1 / metabolism
Mitogen-Activated Protein Kinase 3 / metabolism
Oxidative Stress / drug effects,  physiology*
Ribosomal Protein S6 Kinases, 70-kDa / metabolism
Tissue Inhibitor of Metalloproteinase-2 / metabolism
Xanthine / pharmacology
Xanthine Oxidase / pharmacology
Chemical
Reg. No./Substance:
127497-59-0/Tissue Inhibitor of Metalloproteinase-2; 69-89-6/Xanthine; EC 1.17.3.2/Xanthine Oxidase; EC 2.7.11.1/Ribosomal Protein S6 Kinases, 70-kDa; EC 2.7.11.24/Mitogen-Activated Protein Kinase 1; EC 2.7.11.24/Mitogen-Activated Protein Kinase 3; EC 3.4.24.-/Matrix Metalloproteinases, Membrane-Associated; EC 3.4.24.-/Metalloendopeptidases; EC 3.4.24.24/Matrix Metalloproteinase 2

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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