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LIVER AND BILIARY TRACT
1Third Department of Internal Medicine, Nara Medical University, Nara; and 2Third Department of Internal Medicine, School of Medicine, Kagawa University, Kagawa, Japan
Submitted 22 September 2004 ; accepted in final form 29 November 2004
It is widely recognized that activated hepatic stellate cells (HSC) play a pivotal role in development of liver fibrosis. A platelet-derived growth factor (PDGF) is the most potent mitogen for HSC. The aim of this study was to examine the effect of imatinib mesylate (STI-571, Gleevec), a clinically used PDGF receptor (PDGFR) tyrosine kinase inhibitor, on development of experimental liver fibrosis. The rat model of pig serum-induced hepatic fibrosis was used to assess the effect of daily oral administration of STI-571 on the indexes of fibrosis. STI-571 markedly attenuated development of liver fibrosis and hepatic hydroxyproline and serum fibrosis markers. The number of 
-smooth muscle actin-positive cells and mRNA expression of 2-(I)-procollagen, tissue inhibitor of metalloproteinases-1, and transforming growth factor-
were also significantly suppressed by STI-571. Our in vitro study showed that STI-571 markedly attenuated PDGF-BB-induced proliferation and migration and -SMA and 2-(I)-procollagen mRNA of activated HSC in a dose-dependent manner. STI-571 also significantly attenuated PDGF-BB-induced phosphorylation of PDGFR-, MEK1/2, and Akt in activated HSC. Because STI-571 is widely used in clinical practice, it may provide an effective new strategy for antifibrosis therapy.
platelet-derived growth factor; hepatic stellate cell
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