الفهرس 
Carbon Tetrachloride HepatotoxicityOnly 14 pages are availabe for public view
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Abstract
The aim of this study was to investigate the potential anti-fibrotic effects of imatinib and nilotinib in vivo using experimental liver fibrosis induced by thioacetamide and carbon tetrachloride in rats. Besides, the molecular mechanisms involved in these effects were unraveled using hepatic stellate cells cultures (LX-2 cells and primary rat HSCs). Regarding in vivo experiments, it was found that nilotinib is a potent anti-fbrotic agent. Besides, it was observed that nilotinib reduces hepatic oxidative stress and injury. Unlike nilotinib, imatinib when used at a low or moderate dose in rats, it exhibited only a trend to decrease liver fibrosis. At a relatively high dose level, although imatinib exhibited anti-fibrotic activity, it was overwhelmed by hepatotoxicity. Regarding in vitro experiments, it was found that both imatinib and nilotinib inhibited PDGF-BB-induced chemotaxis and COL1A1 mRNA synthesis in LX-2 cells in a dose dependent manner. Besides, nilotinib (10 and 20 µM) and, to a lesser extent, imatinib (10 and 20 µM) inhibited TGF-β1-induced COL1A1 mRNA synthesis in LX-2 cells in a dose dependent manner. However, TGF-β1-induced TGF-β1 mRNA synthesis in LX-2 cells was inhibited only by nilotinib (10 and 20 µM). In addition, nilotinib, but not imatinib, when applied on LX-2 cells at 10 and 20 µM for 24 hr resulted in approximately 40% and 65% total apoptosis, respectively. Nilotinib effects on LX-2 were confirmed on activated rat HSCs transforming to myofibroblasts (MFBs) at various timing (day 5, 8 and 11), but it did not induce apoptosis of rat quiescent cells (day 1-3). Nilotinib (20 μM) suppressed spontaneous activation of rat HSCs transforming to MFBs, as denoted by α-SMA protein expression level. Beside apoptosis, nilotinb induced autophagic cell death of HSCs. The study also revealed novel targets for nilotinib, which are histone deaceylases (HDACs) 1, 2 and 4 that have been reported to be upregulated in liver fibrosis.