Transforming growth factor-β1 and mannose 6-phosphate/insulin-like growth factor-II receptor expression during intrahepatic bile duct hyperplasia and biliary fibrosis in the rat

Abstract

These studies investigate the role of transforming growth factor-beta 1, a potent inhibitor of epithelial cell proliferation and stimulator of extracellular matrix biosynthesis, during intrahepatic bile duct hyperplasia and biliary fibrosis. These pathogenic responses were induced in rats by common bile duct ligation. Bile duct cell replication, measured by the bromodeoxyuridine labeling index, was significantly increased 24 hr after common bile duct ligation. This response diminished to baseline by 1 wk. Liver collagen content, determined by quantification of hydroxyproline, was increased significantly after 1 wk of common bile duct ligation, and by 4 wk was increased by a factor of 4. Immunohistochemistry revealed low levels of TGF-beta 1 in normal intrahepatic bile duct epithelium. In contrast, the bile duct epithelium in bile duct-ligated rats stained strongly positive for transforming growth factor-beta 1 at 1 and 4 wk after ligation. These results suggest that transforming growth factor-beta 1 may play a role in both the termination of the bile duct epithelial cell proliferative response and the induction of fibrogenesis after common bile duct ligation. In addition, the mannose 6-phosphate/insulin-like growth factor II receptor was up-regulated in hyperplastic bile duct epithelium 1 and 4 wk after ligation. Because the mannose 6-phosphate/insulin-like growth factor-II receptor has been shown to facilitate the proteolytic activation of transforming growth factor-beta 1, these results suggest that the bile duct epithelium may also be involved in the activation of transforming growth factor-beta 1.

Potential therapeutic effects of a traditional Chinese formulation, BJ-JN, on liver fibrosis induced by carbon tetrachloride in rats

“…Oxidative stress has been considered as a major molecular mechanism involved in CCl 4 toxicity (Hernandez-Munoz et al, 1997). Peroxidation of lipids was involved in the regulation of collagen gene expression by hepatic stellate cells (Saperstein et al, 1994) and an inverse correlation between lipid peroxidation and collagenase activity has been reported in CCl 4 -treated rats (Gasso et al, 1996). Previous reports showed that oxidative stresses play an important role for the inactivation of Kupffer cells in the initial of CCl 4 -induced rat liver fibrosis (Luckey and Petersen, 2001;Muriel and Escobar, 2003).…”

The role of TGF-β1 and cytokines in the modulation of liver fibrosis by Sho-saiko-to in rat's bile duct ligated model

“…(A) Sham-operated rat; (B) BDL without treatment, these reddish-brown hepatocyte indicated the TGF-␤1 positive staining; (C) BDL and treated with TJ-9 at a dose of 0.5 g/(kg BW day), these reddish-brown staining were reduced. brogenic animal models, including of carbon tetrachloride, thioacetamide, Schistosoma mansoni and bile duct ligation (Armendariz-Borunda et al, 1993;Kresina et al, 1994;Saperstein et al, 1994). Furthermore, over expression of mature TGF-␤1 in transgenic mice results in developed liver fibrosis (Sanderson et al, 1995).…”

“…Briefly, the samples were incubated overnight with a 1:200 dilution of anti-TGF-␤1 antibody (Sigma, USA). After washing, the samples were detected with biotinylated goat anti-mouse antibody and peroxidaselabelled streptavidin/biotin complex, using aminoethylcarbazol as substrate (Saperstein et al, 1994).…”

Receptors, endocytosis, and trafficking: the biological basis of targeted delivery of antisense and siRNA oligonucleotides

“…Thus selectively targeting anti-fibrotic agents to hepatic stellate cells may provide effective and safe treatment for liver fibrosis. Mannose-6-phosphate/insulin growth factor type 2 receptor (M6P/IGF2R) is a primary target for HSC targeting, since its expression is increased when HSCs are activated during fibrosis (Saperstein et al, 1994). M6P/IGF2R targeting can be achieved by coupling M6P moiety to drug or their carriers (Beljaars et al, 1999).…”