粉防己碱对肝星状细胞及肝纤维化大鼠的抗纤维化作用。
Antifibrotic effects of tetrandrine on hepatic stellate cells and rats with liver fibrosis.
作者信息
Hsu Yi-Chao, Chiu Yung-Tsung, Cheng Ching-Chang, Wu Ching-Fen, Lin Yun-Lian, Huang Yi-Tsau
机构信息
Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
出版信息
J Gastroenterol Hepatol. 2007 Jan;22(1):99-111. doi: 10.1111/j.1440-1746.2006.04361.x.
BACKGROUND
Anti-inflammation strategies are one of the proposed therapeutic approaches to hepatic fibrosis. Tetrandrine (C(38)H(42)O(8)N(2), 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.
METHODS
A cell line of rat hepatic stellate cells (HSC-T6) was stimulated with transforming growth factor-beta1 (TGF-beta1) or tumor necrosis factor-alpha (TNF-alpha). The inhibitory effects of Tet on the nuclear factor kappaB (NFkappaB) 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.
RESULTS
Tetrandrine (0.5-5.0 micromol/L) concentration-dependently inhibited NFkappaB transcriptional activity induced by TNF-alpha, including IkappaBalpha phosphorylation and mRNA expressions of ICAM-1 in HSC-T6 cells. In addition, Tet also inhibited TGF-beta1-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 NFkappaB-positive cells were decreased in the fibrotic livers by Tet and silymarin treatment. In addition, mRNA expression of ICAM-1, alpha-SMA, and TGF-beta1 was attenuated by Tet treatment. Moreover, levels of plasma aspartate aminotransferase and alanine aminotransferase activities were reduced by Tet and silymarin treatment.
CONCLUSION
Tetrandrine exerts antifibrotic effects in both HSC-T6 cells and in rats with DMN-induced fibrosis.
背景
抗炎策略是肝纤维化的一种治疗方法。粉防己碱（C₃₈H₄₂O₈N₂，分子量：622；Tet）是从中药粉防己中分离出的一种生物碱，已被证明在肺部疾病中具有抗炎活性。本研究的目的是探讨粉防己碱对肝纤维化的体内外作用。
方法
用转化生长因子-β1（TGF-β1）或肿瘤坏死因子-α（TNF-α）刺激大鼠肝星状细胞系（HSC-T6）。评估粉防己碱对核因子κB（NFκB）信号级联以及包括细胞间黏附分子-1（ICAM-1）和α-平滑肌肌动蛋白（α-SMA）分泌在内的分子标志物的抑制作用。通过给大鼠腹腔注射二甲基亚硝胺（DMN）4周诱导肝纤维化。将纤维化大鼠随机分为四组之一：溶剂对照组（0.7%羧甲基纤维素，CMC）、粉防己碱（1mg/kg）组、粉防己碱（5mg/kg）组或水飞蓟宾（50mg/kg）组，从DMN给药1周后开始，每组每天经口灌胃给药2次，持续3周。在研究结束时，对肝组织进行纤维化评分并分析纤维化的分子标志物。
结果
粉防己碱（0.5 - 5.0μmol/L）浓度依赖性地抑制TNF-α诱导的NFκB转录活性，包括HSC-T6细胞中IκBα磷酸化和ICAM-1的mRNA表达。此外，粉防己碱还抑制TGF-β1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处理大鼠相比，高剂量粉防己碱（1.3±0.3）处理的DMN处理大鼠肝脏的纤维化评分显著降低。粉防己碱或水飞蓟宾处理均显著降低了DMN大鼠的肝胶原含量。双重染色结果显示，粉防己碱和水飞蓟宾处理使纤维化肝脏中α-SMA和NFκB阳性细胞减少。此外，粉防己碱处理使ICAM-1、α-SMA和TGF-β1的mRNA表达减弱。而且，粉防己碱和水飞蓟宾处理降低了血浆天冬氨酸氨基转移酶和丙氨酸氨基转移酶活性水平。
结论
粉防己碱在HSC-T6细胞和DMN诱导的纤维化大鼠中均发挥抗纤维化作用。
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