Fang Dazheng, He Ying, Luan Zhou
Department of Hepatobiliary Surgery, Dongfeng General Hospital, Hubei University of Medicine, Shiyan, Hubei 442008, P.R. China.
Department of Ophthalmology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430014, P.R. China.
Exp Ther Med. 2017 Nov;14(5):4839-4845. doi: 10.3892/etm.2017.5156. Epub 2017 Sep 21.
Obstructive jaundice, owing to biliary obstruction, has been illustrated to trigger various biochemical, histological and immunological changes, leading to liver damage or even failure. The detailed molecular mechanism of simvastatin (Sim) involvement in liver regeneration during obstructive jaundice progression remains poorly elucidated. In the present study, an acute obstructive jaundice rat model was established by ligation and division of common bile duct, which was used to investigate the effects of Sim as a hepatoprotective treatment. Male Sprague-Dawley rats were randomly divided into four groups: Sham-operated, bile duct ligation (BDL) plus saline treatment [0.02 mg/kg/d, intraperitoneally (i.p.)], BDL plus low-dose Sim treatment (0.02 mg/kg, i.p.) and BDL plus high-dose Sim treatment (0.2 mg/kg, i.p.). During this experiment, the BDL+normal saline (NS) group demonstrated increased levels of transforming growth factor-β1 (TGF-β1) expression. Furthermore, Sim-treated animals demonstrated significantly downregulated TGF-β1 expression and improved liver function vs. the BDL+NS group, indicating a TGF-β1 antagonizing function. Additionally, Sim increased hepatocyte DNA synthesis in BDL rats compared to both the BDL+NS and Sham group. Apoptosis was increased in BDL+NS compared to the Sham group, and Sim markedly reduced hepatocyte apoptosis in the BDL group. Moreover, analysis of TGF-β1 signaling pathways demonstrated that there was an increased hepatic TGF-β1 and Smad3 expression in the BDL group, which was attenuated in the presence of Sim. In contrast to TGF-β1, Sim induced the activity of the Smad7 (an inhibitor of TGF-β1 signaling) mRNA and Smad7 protein expression. Sim displays hepatoprotective effects in liver cells via the upregulation of Smad7 expression and impaired TGF-β signaling. Furthermore, the observations of the present study may provide evidence on the mechanism behind Sim blunting TGF-β1 signaling, which is used to ameliorate the complication of liver damage and reduce the mortality rates associated with obstructive jaundice.
由于胆管阻塞导致的梗阻性黄疸已被证明会引发各种生化、组织学和免疫学变化，从而导致肝损伤甚至肝衰竭。辛伐他汀（Sim）在梗阻性黄疸进展过程中参与肝脏再生的详细分子机制仍不清楚。在本研究中，通过结扎和切断胆总管建立急性梗阻性黄疸大鼠模型，用于研究Sim作为一种肝保护治疗的效果。雄性Sprague-Dawley大鼠随机分为四组：假手术组、胆管结扎（BDL）加生理盐水治疗组[0.02 mg/kg/d，腹腔注射（i.p.）]、BDL加低剂量Sim治疗组（0.02 mg/kg，i.p.）和BDL加高剂量Sim治疗组（0.2 mg/kg，i.p.）。在本实验过程中，BDL+生理盐水（NS）组显示转化生长因子-β1（TGF-β1）表达水平升高。此外，与BDL+NS组相比，Sim治疗的动物TGF-β1表达明显下调，肝功能得到改善，表明其具有TGF-β1拮抗功能。此外，与BDL+NS组和假手术组相比，Sim增加了BDL大鼠肝细胞的DNA合成。与假手术组相比，BDL+NS组细胞凋亡增加，而Sim显著降低了BDL组肝细胞凋亡。此外，对TGF-β1信号通路的分析表明，BDL组肝脏TGF-β1和Smad3表达增加，而在Sim存在的情况下这种增加减弱。与TGF-β1相反，Sim诱导了Smad7（TGF-β1信号抑制剂）mRNA的活性和Smad7蛋白表达。Sim通过上调Smad7表达和损害TGF-β信号通路对肝细胞发挥肝保护作用。此外，本研究的观察结果可能为Sim减弱TGF-β1信号通路的机制提供证据，该机制可用于改善肝损伤并发症并降低与梗阻性黄疸相关的死亡率。
