Objective      To investigate the role of integrin αvβ6 in the pathogenesis of biliary fibrosis following orthotopic liver transplantation (OLT)

and to explore the new therapeutic strategies for graft cholangiopathy (GC).       Methods      A total of 45 male FVB/N mice were randomly divided into 3 groups

that is

sham-operation group (control group)

OLT group

and OLT with integrin αvβ6 antagonist EMD527040 group. The non-arterialized mouse OLT model with 12 hours’ cold-preservation was used in the later 2 groups. The expression of αvβ6 and fibrosis-related transcriptors were determined by quantitative reverse-transcription polymerase chain reaction (RT-PCR)

and serum levels of alanine aminotransferase (ALT)

γ-glutamyltransferase (GGT)

alkaline phosphatase (ALP) and liver hydroxyproline (Hyp) content were measured. Masson Trichrome staining were performed to determine the morphological changes of intrahepatic bile ducts.       Results      Cold preservation/reperfusion injury (CPRI) combined with hepatic artery occlusion induced biliary fibrosis of liver allograft in the mice. During the pathogenesis of biliary fibrosis

the mRNA expression of integrin αvβ6 was up-regulated to 13.2-fold and 32.5-fold higher than control in 4 and 6 weeks after transplantation

respectively. The relative hepatic Hyp content was increased by 87.5% and 124.4% at the same time points when compared with control. Inhibition of integrin αvβ6 significantly retarded biliary fibrosis progression and improved hepatic function following OLT.       Conclusion       Ischemia-reperfusion injury is the major cause of bile duct injury after OLT. Integrin αvβ6 plays a key role in the pathogenesis of bile duct injury and repair

which might be a novel marker of biliary fibrosis and an attractive target for anti-fibrotic therapies in the treatment of GC following OLT.