Antifibrotic effects of tetrandrine on hepatic stellate cells and rats with liver fibrosis
Antifibrotic effects of tetrandrine on hepatic stellate cells and rats with liver fibrosis
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DOI：
10.1111/j.1440-1746.2006.04361.x
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发表时间：
2007-01-01
影响因子：
4.1
通讯作者：
Huang, Yi-Tsau
中科院分区：
文献类型：
--
作者：
Hsu, Yi-Chao;Chiu, Yung-Tsung;Huang, Yi-Tsau
抗炎策略是肝纤维化的治疗方法之一。汉防己甲素（C38 H42 O 8 N2，分子量：622;泰特）是从中药粉防己中提取的一种生物碱，具有抗炎作用。为探讨泰特对大鼠肝星状细胞（HSC-T6）的抗肝纤维化作用，采用转化生长因子-β 1（TGF-β 1）和肿瘤坏死因子-α（TNF-α）刺激HSC-T6细胞。评价了泰特对核因子κ B（NF kappa B）信号级联和分子标志物（包括细胞间粘附分子-1（ICAM-1）和α-平滑肌肌动蛋白（α-SMA）分泌的抑制作用。用二甲基亚硝胺（DMN）诱导大鼠纤维化4周。将纤维化大鼠随机分配到四个组中的一个：媒介物（0.7%羧甲基纤维素，CMC）、泰特（1 mg/kg）、泰特（5 mg/kg）或水飞蓟素（50 mg/kg），在DMN施用1周后开始，每天两次通过管饲法给予每一组，持续3周。汉防己甲素（0.5-5.0 μ mol/L）浓度依赖性地抑制TNF-α诱导的HSC-T6细胞NF-κ B转录活性，包括I-κ B α磷酸化和ICAM-1 mRNA表达。此外，泰特还抑制TGF-β 1诱导的HSC-T6细胞中α-SMA分泌和胶原沉积。与接受生理盐水的DMN处理大鼠（2.0 +/- 0.2）相比，接受高剂量泰特的DMN处理大鼠的肝脏纤维化评分（1.3 +/- 0.3）显著降低。泰特和水飞蓟素均能显著降低DMN大鼠肝脏胶原含量。双染结果显示，泰特和水飞蓟素处理的纤维化肝脏中α-SMA和NF κ B阳性细胞减少。此外，泰特处理减弱了ICAM-1、α-SMA和TGF-β 1的mRNA表达。此外，泰特和水飞蓟素处理后，血浆天冬氨酸转氨酶和丙氨酸转氨酶活性均降低。粉防己碱在HSC-T6细胞和DMN诱导的纤维化大鼠中均具有抗纤维化作用。
Anti-inflammation strategies are one of the proposed therapeutic approaches to hepatic fibrosis. Tetrandrine (C38H42O8N2, molecular weight: 622; Tet), an alkaloid isolated from the Chinese medicinal herb Stephania tetrandra, has been shown to exert anti-inflammatory activity in pulmonary diseases. The purpose of the present study was to investigate the in vitro and in vivo effects of Tet on hepatic fibrosis.A cell line of rat hepatic stellate cells (HSC-T6) was stimulated with transforming growth factor-beta 1 (TGF-beta 1) or tumor necrosis factor-alpha (TNF-alpha). The inhibitory effects of Tet on the nuclear factor kappa B (NF kappa B) signaling cascade and molecular markers including intercellular adhesion molecule-1 (ICAM-1) and alpha-smooth muscle actin (alpha-SMA) secretion were assessed. Fibrosis was induced by dimethylnitrosamine (DMN) administration in rats for 4 weeks. Fibrotic rats were randomly assigned to one of the four groups: vehicle (0.7% carboxyl methyl cellulose, CMC), Tet (1 mg/kg), Tet (5 mg/kg), or silymarin (50 mg/kg), each given by gavage twice daily for 3 weeks starting after 1 week of DMN administration. At the end of the study, liver tissues were scored for fibrosis and analyzed for molecular markers of fibrosis.Tetrandrine (0.5-5.0 mu mol/L) concentration-dependently inhibited NF kappa B transcriptional activity induced by TNF-alpha, including I kappa B alpha phosphorylation and mRNA expressions of ICAM-1 in HSC-T6 cells. In addition, Tet also inhibited TGF-beta 1-induced alpha-SMA secretion and collagen deposition in HSC-T6 cells. Fibrosis scores of livers from DMN-treated rats with high-dose Tet (1.3 +/- 0.3) were significantly reduced in comparison with DMN-treated rats receiving saline (2.0 +/- 0.2). Hepatic collagen content of DMN rats was significantly reduced by either Tet or silymarin treatment. Double-staining results showed that alpha-SMA- and NF kappa B-positive cells were decreased in the fibrotic livers by Tet and silymarin treatment. In addition, mRNA expression of ICAM-1, alpha-SMA, and TGF-beta 1 was attenuated by Tet treatment. Moreover, levels of plasma aspartate aminotransferase and alanine aminotransferase activities were reduced by Tet and silymarin treatment.Tetrandrine exerts antifibrotic effects in both HSC-T6 cells and in rats with DMN-induced fibrosis.