Role of Integrin αvβ6 in the Pathogenesis of Ischemia-Related Biliary Fibrosis After Liver Transplantation

Abstract

Biliary fibrosis has been referred to as the "final common pathway" of acute and chronic bile duct injury after orthotopic liver transplantation (OLT). We studied the role of integrin αvβ6 in the pathogenesis of ischemia-related biliary fibrosis after OLT. The mouse nonarterialized OLT model with prolonged cold ischemia time was used in this study. A total of 54 FVB/N mice were divided into three groups: sham-operated group (sham, n=18), OLT group that was given the blocking antibody to integrin αvβ6 (OLT+antibody, n=18), and OLT group that was given the isotype control immunoglobulin G (OLT+vehicle, n=18). The expression of αvβ6 and major fibrosis-related genes were studied by real-time polymerase chain reaction and immunohistochemistry. Serum and bile were collected and analyzed biochemically. The histopathologic evaluation was performed to determine the severity of biliary fibrosis and bile duct injury. Integrin αvβ6 was highly expressed on newly formed bile ducts because of cholangiocyte proliferation and was gradually upregulated with the progression of biliary fibrosis after liver transplantation. αvβ6 transcripts closely correlated with fibrosis stages but not bile duct injury severity. Inhibition of αvβ6 attenuated peribiliary collagen deposition remarkably, induced significant downregulation of fibrogenic genes, and improved hepatic function. Integrin αvβ6 is strongly induced de novo in newly formed bile ducts because of cholangiocyte proliferation during ischemia-related biliary fibrogenesis after liver transplantation. Inhibition of αvβ6 could retard the progression of biliary fibrosis of liver allograft significantly, suggesting that αvβ6 is a potential target for the treatment of ischemic biliary complications.