Inhibition of Proliferative Activity of Pulmonary Fibroblasts by Tetrandrine

Nan

Pharmacology & Toxicology

et al. 2000

Tetrandrine, an alkaloid isolated from the Chinese medicinal herb Stephania tetrandra, has been shown to elicit antifibrotic effects in various cell types. In the present study, the effect of tetrandrine on liver fibrosis was investigated by using bile duct ligation and scission in rats as a model of hepatic fibrosis. Treatment with tetrandrine in fibrotic rats reduced serum aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase levels to 72%, 52% and 51% that of controls at 10 mg/kg/day, respectively. Liver hydroxyproline contents in tetrandrine-treated rats with bile duct ligation and scission were also reduced to 65% of that of control rats with bile duct ligation and scission at 10 mg/kg/day. The morphological characteristics of fibrotic liver, which appeared in control bile duct ligation and scission group, were improved in tetrandrine-treated bile duct ligation and scission group. We also examined the effect of tetrandrine on cultured rat hepatic stellate cells, which plays an important role in the pathogenesis of hepatic fibrosis, activation to investigate whether it could act mainly by direct action on rat hepatic fibroblastic cells. In cultured rat hepatic stellate cells, tetrandrine reduced DNA synthesis to 57% of control hepatic stellate cells at 10 mg/ml without affecting cell viability. Smooth muscle-a-actin expression, the phenotypic marker of activated hepatic stellate cells, was also decreased. We conclude that tetrandrine has an antifibrotic effect on liver fibrosis in rats induced by bile duct ligation and scission, indicating that it might exert a direct effect on rat hepatic stellate cells.Hepatic fibrosis is a consequence of severe liver damage that occurs in many patients with chronic liver disease. Regardless of many different causes, hepatic fibrosis is characterized by increased and altered deposition of newly formed extracellular matrix components such as collagens, proteoglycans, fibronectin and hyaluronic acid (Friedman 1993), leading to the complication of portal hypertension and hepatic failure.In the injured liver, these extracellular matrix components are produced in hepatic stellate cells in the space of Disse, which function in intact liver lobules as the primary storage area for retinoids (Hendrisks et al. 1985). During the course of ongoing liver fibrogenesis, hepatic stellate cells acquire myofibroblastic features, proliferate (Friedman et al. 1989;Hautekeete & Geerts 1997), synthesize increased amounts of extracellular matrix components (Shiratori et al. 1987) and express smooth muscle-a-actin . The transformation of hepatic stellate cells into myofibroblast-like cells is recognized as a critical step in hepatic fibrosis. Therefore, this cell type is an important target for antifibrotic therapy.Tetrandrine is a bis-benzyl isoquinoline alkaloid derived from Stephania tetrandra (Moore). This compound has been characterized pharmacologically to exhibit hypotensive, immunosuppressive properties (Sutter & Wang 1993), and inhibition of lipid perox...

Section: Discussionsupporting

confidence: 68%

mentioning

confidence: 99%

Effect of Tetrandrine on Experimental Hepatic Fibrosis Induced by Bile Duct Ligation and Scission in Rats

Nan

Pharmacology & Toxicology

et al. 2000

“…Tetrandrine is a bis-benzyl isoquiniline alkaloid from the Chinese herb radix Stephania tetrandra S Moore. This compound has been characterized pharmacologically t o e x h i b i t hy p o t e n s ive, a n t i -i n f l a m m a t o r y, a n d immunosuppressive properties, to inhibit lipid peroxidation, and to have an antifibrogenic activity against pulmonary fibroblasts and an inhibitory effect on typeⅠand Ⅲ collagen gene mRNA levels in the lung tissue of rats [11][12][13] . The dried root of S. tetrandra is one of the traditional Chinese medicines that have long been used to treat human liver fibrosis and cirrhosis [14] .…”

Section: Introductionmentioning

confidence: 99%

Tetrandrine stimulates the apoptosis of hepatic stellate cells and ameliorates development of fibrosis in a thioacetamide rat model

Yin

Lian²,

Piao³

et al. 2007

WJG

AIM:To investigate the therapeutic effect of tetrandrine on liver fibrosis induced by thioacetamide in rats in vivo and in vitro . METHODS:In vitro study: we investigated the effect of tetrandrine on the apoptosis of rat hepatic stellate cells transformed by simian virus 40 (T-HSC/Cl-6), which retains the features of activated cells. In vivo study: hepatic fibrosis was induced in rats by thioacetamide. Tetrandrine was given orally to rats at doses of 5, 10 or 20 mg/kg for 4 wk compared with intraperitoneal injection of interferon-г.

Pharmacology & Toxicology

“…It has also been shown to exhibit antifibrogenic activity against fibroblasts, particularly pulmonary fibroblasts (Reist et al 1993), strong binding to alveolar macrophages (Ma et al 1991), inhibition of proliferative activity of pulmonary fibroblast, and an inhibitory effect on types I and III collagen gene mRNA level in lung tissue of rats (Liu et al 1994).We have previously reported that tetrandrine has an antifibrotic effect on liver fibrosis in rats induced by bile duct ligation and scission and tetrandrine exert a direct inhibition effect on rat hepatic stellate cell activation (Park et al 2000).Previous studies suggest that collagenase activity becomes deficient during evolution of liver fibrosis in animal models and in humans (Takahashi et al 1980;Maruyama et al 1982;Rerez-Tamayo et al 1987), and the studied described earlier suggest that this may be caused by the tissue inhibitor of metalloproteinase overexpression. Continued inhibition of extracellular matrix degradation by the tissue inhibitor of metalloproteinases may block the ability to recover from fibrosis, even after removal of the injury.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Tetrandrine Prevents Tissue Inhibitor of Metalloproteinase‐1 Messenger RNA Expression in Rat Liver Fibrosis

Lee

Nan

Sohn

2001

Tetrandrine, one of the alkaloids isolated from the Chinese herb Radix stephania tetrandra S Moore, has traditionally been used to treat hypertension and silicosis. It has also been shown to exhibit antifibrogenic activity against fibroblasts, particularly pulmonary fibroblasts (Reist et al. 1993), strong binding to alveolar macrophages (Ma et al. 1991), inhibition of proliferative activity of pulmonary fibroblast, and an inhibitory effect on types I and III collagen gene mRNA level in lung tissue of rats (Liu et al. 1994).We have previously reported that tetrandrine has an antifibrotic effect on liver fibrosis in rats induced by bile duct ligation and scission and tetrandrine exert a direct inhibition effect on rat hepatic stellate cell activation (Park et al. 2000).Previous studies suggest that collagenase activity becomes deficient during evolution of liver fibrosis in animal models and in humans (Takahashi et al. 1980;Maruyama et al. 1982;Rerez-Tamayo et al. 1987), and the studied described earlier suggest that this may be caused by the tissue inhibitor of metalloproteinase overexpression. Continued inhibition of extracellular matrix degradation by the tissue inhibitor of metalloproteinases may block the ability to recover from fibrosis, even after removal of the injury. These data suggest that the tissue inhibitor of metalloproteinases play a predominant role in regulating fibrosis by protecting fibrotic extracellular matrix from degradation by collagenase and possibly other metalloproteinases.Therefore, the purpose of the present study was to clarify the effects of a tetrandrine on tissue inhibitor of metalloproteinase-1 and collagen type I were examined in rat fibrotic liver induced by bile duct ligation and scission.Males Sprague-Dawley rats (initial body weight 220-250 g) were used. Rats were anaesthetized with ketamine/rompun and double ligatures were performed on the common