Smad3 Deficiency Counteracts Hepatocyte Apoptosis and Portal Fibrogenesis Induced By Bile Duct Ligation

Misako Sato,Kathleen C Flanders

doi:10.4172/2167-0889.1000145

Abstract

Objectives: Transforming Growth Factor (TGF)-β is reportedly upregulated and plays a critical role in hepatic fibrogenesis. We aim to study the role of the Smad3, a key transcription factor downstream of TGF-β receptors, signaling pathway in the pathogenesis of cholestatic liver injury induced by Bile Duct Ligation (BDL). Materials and methods: We used mice lacking Smad3 (Smad3ex8/ex8), and their wild-type littermates to model hepatic fibrosis using BDL. The underlying biology was investigated using histopathological examination and primary cultures of hepatocytes and biliary epithelial cells. Results: Here we found that mice lacking Smad3 are protected against cholestatic liver injury induced by BDL as evidenced by the absence of hepatocyte apoptosis and portal fibroproliferative responses,including excessive collagen deposition and periductalmyofibroblast proliferation. Smad3-null mice are also shown to reverse the hepatic TGF-β1 upregulation after BDL. In vitro study demonstrates that TGF-β1 expression in primary hepatocytes and intrahepatic biliary epithelial cells is amplified by TGF-β1 itself through a positive feedback loop dependent on Smad3. Culture of primary hepatocytes confirmsthat Smad3 is indispensable for TGF-β1-induced apoptosis. Conclusions: The data demonstrate that Smad3 plays principal roles in the pathogenesis of BDL-induced cholestatic liver injury and suggest that intervention in this pathway may provide a novel therapeutic approach in the treatment of hepatic fibrosis.

Highlights

Hepatic fibrosis results from chronic injury due to various causes and leads to the irreversible and massive accumulation of Extracellular Matrix (ECM) proteins [1,2]
The data demonstrate that Smad3 plays principal roles in the pathogenesis of Bile Duct Ligation (BDL)-induced cholestatic liver injury and suggest that intervention in this pathway may provide a novel therapeutic approach in the treatment of hepatic fibrosis
Cholestatic liver injury produces portal fibrosis accompanied by periductal myofibroblast proliferation and necrotic or apoptotic periportal hepatocellular damage, leading to biliary cirrhosis characterized by nodule formation and scarring with portal-portal fibrous septa

Summary

Introduction

Hepatic fibrosis results from chronic injury due to various causes and leads to the irreversible and massive accumulation of Extracellular Matrix (ECM) proteins [1,2]. The morphological pattern of advanced hepatic fibrosis is similar, the characteristics of the pathogenetic insults may differ in the early stages of hepatic disease. Cholestatic liver injury produces portal fibrosis accompanied by periductal myofibroblast proliferation and necrotic or apoptotic periportal hepatocellular damage, leading to biliary cirrhosis characterized by nodule formation and scarring with portal-portal fibrous septa. Chronic viral hepatitis produces cirrhosis that features scarring with portal-central fibrous septa [3]. Several lines of evidence have pointed to Hepatic Stellate Cells (HSC) as being a principal culprit in hepatic fibrosis after transdifferentiating from quiescent HSC into fibrogenic myofibroblasts [4,5]. A variety of hepatic cell types other than HSC have recently been shown to undergo myofibroblastic transition, participating in hepatic fibrogenesis and tissue remodeling [2,3,6,7]

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