Anti-fibrotic effects of tetrandrine on bile-duct ligated rats

Tetrandrine (Tet) (C38H42O8N2; molecular weight, 622), an alkaloid isolated from the Chinese medicinal herb Stephania tetrandra, has been shown to elicit anti-inflammatory and anti-fibrotic effects in pulmonary diseases, but the mechanism of action has yet to be investigated. In this study, we tested whether Tet exerts anti-fibrotic effects on rat hepatic fibrosis through anti-NFkappaB pathways. After bile-duct ligation, rats were given Tet (1 or 5 mg/kg) or silymarin (50 mg/kg, as a positive control) by gavage twice daily for 3 weeks. Liver sections were taken for Sirius red quantitative scoring, immunofluorescence double staining of alpha-smooth muscle actin (alpha-SMA) and NFkappaB, and for quantitative determinations of the mRNA expression levels of TGF-beta1, alpha-SMA, collagen 1alpha2, inducible nitric oxide synthase (iNOS), intercellular adhesion molecule 1 (ICAM-1), metallothionein, vascular endothelial growth factor (VEGF), and VEGF type II receptor (VEGFR2) genes. The results showed that both Tet and silymarin treatment significantly reduced the fibrosis scores and hepatic collagen content of BDL rats, compared with no treatment. Both Tet and silymarin treatments decreased the number of alpha-SMA- and NFkappaB-positive cells in fibrotic livers. Moreover, Tet and silymarin treatments attenuated the mRNA expression levels of TGF-beta1,alpha-SMA, collagen 1alpha2, iNOS, ICAM-1, VEGF, and VEGFR2 genes, and induced the mRNA expression of the metallothionein gene. This study suggests that the anti-fibrotic effects of Tet were related to the reduction of fibrosis-related gene transcription, the attenuation of NFkappaB-activated pathways, and the induction of metallothionein gene transcription in the livers of BDL rats.