Comparison of imatinib, nilotinib and silymarin in the treatment of carbon tetrachloride-induced hepatic oxidative stress, injury and fibrosis.
Comparison of imatinib, nilotinib and silymarin in the treatment of carbon tetrachloride-induced hepatic oxidative stress, injury and fibrosis.
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DOI：
10.1016/j.taap.2011.02.004
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发表时间：
2011-04-15
影响因子：
3.8
通讯作者：
Ibrahim TM
中科院分区：
文献类型：
--
作者：
Shaker ME;Zalata KR;Mehal WZ;Shiha GE;Ibrahim TM
目前缺乏有效且耐受性良好的抗纤维化药物。因此，本研究旨在研究伊马替尼、尼洛替尼和水飞蓟素对四氯化碳（CCl 4）大鼠模型中已建立的肝纤维化的潜在抗纤维化作用。雄性Wistar大鼠接受CCl 4每周两次腹腔注射，持续8周，以及在CCl 4中毒的最后4周期间每天腹腔注射伊马替尼（10和20 mg/kg）、尼洛替尼（10和20 mg/kg）和水飞蓟素（100 mg/kg）。在研究结束时，通过分析肝功能检查和肝脏氧化应激参数来评价肝损伤。通过组织病理学和形态计量学以及胶原和4-羟脯氨酸含量评估肝纤维化。如肝功能检查和组织病理学所示，尼洛替尼（20 mg/kg）是对抗CCl 4诱导的肝损伤的最有效治疗。尼洛替尼（10 mg/kg）、尼洛替尼（20 mg/ kg）和水飞蓟素（100 mg/kg）治疗使CCl 4治疗大鼠的肝纤维化平均评分分别降低31%、68%和47%，肝胶原含量分别降低47%、49%和18%。肝脏形态学评价和4-羟脯氨酸含量显示，尼洛替尼（20 mg/kg）和伊马替尼（20 mg/kg）显著改善了CCl 4诱导的纤维化。与尼洛替尼不同，伊马替尼（20 mg/kg）表现出某种肝损伤，表现为血清转氨酶和总胆红素水平升高，肝脏总硝酸盐/亚硝酸盐含量升高，以及苏木精伊红染色可见的特征性异核细胞增多症。总之，本研究提供了尼洛替尼具有抗纤维化活性的证据，并表明其可能在人类肝纤维化治疗中具有价值。
Effective and well-tolerated anti-fibrotic drugs are currently lacking. Therefore, this study was carried out to investigate the potential anti-fibrotic effects of imatinib, nilotinib and silymarin on established hepatic fibrosis in the carbon tetrachloride (CCl4) rat model. Male Wistar rats received intraperitoneal injections of CCl4 twice weekly for 8 weeks, as well as daily intraperitoneal treatments of imatinib (10 and 20 mg/kg), nilotinib (10 and 20 mg/kg) and silymarin (100 mg/kg) during the last 4 weeks of CCl4-intoxication. At the end of the study, hepatic damage was evaluated by analysis of liver function tests and hepatic oxidative stress parameters. Hepatic fibrosis was evaluated by histopathology and morphometry, as well as collagen and 4-hydroxyproline contents. Nilotinib (20 mg/kg) was the most effective treatment to counteract CCl4-induced hepatic injury as indicated by liver function tests and histopathology. Nilotinib (10 mg/kg), nilotinib (20 mg/ kg) and silymarin (100 mg/kg) treatments reduced the mean score of hepatic fibrosis by 31%, 68% and 47%, respectively, and hepatic collagen content by 47%, 49% and 18%, respectively in CCl4-treated rats. Hepatic morphometric evaluation and 4-hydroxyproline content revealed that CCl4-induced fibrosis was ameliorated significantly by nilotinib (20 mg/kg) and imatinib (20 mg/kg). Unlike nilotinib, imatinib (20 mg/kg) showed some sort of hepatic injury evidenced by elevation of serum aminotransferases and total bilirubin levels, and hepatic total nitrate/nitrite content, as well as characteristic anisonucleosis visualized with the hematoxylineosin staining. In conclusion, this study provides the evidence that nilotinib exerts anti-fibrotic activity and suggests that it may be valuable in the treatment of hepatic fibrosis in humans.
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影响因子：
4.8
作者：
Kumar, S;Bharti, A;Kufe, D
通讯作者：
Kufe, D
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Distler, Joerg H. W.;Juengel, Astrid;Distler, Oliver
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Distler, Oliver