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1 Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
2 Third Department of Internal Medicine, School of Medicine, Kagawa University, Miki-cho, Kagawa, Japan
* To whom correspondence should be addressed. E-mail: yoshijih{at}naramed-u.ac.jp.
It is now widely recognized that the activated hepatic stellate cells (HSC)
play a pivotal role in the liver fibrosis development. A platelet-derived
growth factor (PDGF) is the most potent mitogen for the HSC. The aim of
this study was to examine the effect of imatinib mesylate (STI571;
Gleevec), which is a clinically used PDGF receptor (PDGFR) tyrosine
kinase inhibitor, on the experimental liver fibrosis development. The rat
model of pig serum-induced hepatic fibrosis was used to assess the effect of
daily oral administration of STI571 on the indices of fibrosis. STI571
markedly attenuated the liver fibrosis development, hepatic hydroxyproline
and serum fibrosis markers. The number of 
-smooth muscle actin (-
SMA)-positive cells, and the mRNA expressions of 2-(I)-procollagen,
tissue inhibitor of metalloproteinases-1 (TIMP-1), and transforming growth
factor-
(TGF-) were also significantly suppressed by STI571 treatment.
Our in vitro study showed that STI571 markedly attenuated the PDGF-BB-induced
proliferation, migration, and -SMA, 2-(I)-procollagen mRNA of
the activated HSC in a dose-dependent manner. STI571 also significantly
attenuated the PDGF-BB-induced phosphorylation of PDGFR-, MEK1/2,
and Akt in the activated HSC. Because STI571 is widely used in the
clinical practice, this drug may provide an effective new strategy for anti-fibrosis therapy.
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