Role of αvβ6 integrin in acute biliary fibrosis

Acute biliary obstruction leads to periductal myofibroblasts and fibrosis, the origin of which is uncertain. Our study provides new information on this question in mice and humans. We show that bile duct obstruction induces a striking increase in cholangiocyte alpha v beta 6 integrin and that expression of this integrin is directly linked to fibrogenesis through activation of transforming growth factor beta (TGF-beta). Administration of blocking antibody to alpha v beta 6 significantly reduces the extent of acute fibrosis after bile duct ligation. Moreover, in beta 6-null mice subjected to the injury, fibrosis is reduced by 50% relative to that seen in wild-type mice, whereas inflammation occurs to the same extent. The data indicate that alpha v beta 6, rather than inflammation, is linked to fibrogenesis. It is known that alpha v beta 6 binds latent TGF beta and that binding results in release of active TGF beta. Consistent with this, intracellular signaling from the TGF beta receptor is increased after bile duct ligation in wild-type mice but not in beta 6(-/-) mice, and a competitive inhibitor of the TGF beta receptor type 11 blocks fibrosis to the same extent as antibody to alpha v beta 6. In a survey of human liver disease, expression of alpha v beta 6 is increased in acute, but not chronic, biliary injury and is localized to cholangiocyte-like cells. Conclusion: Cholangiocytes respond to acute bile duct obstruction with markedly increased expression of alpha v beta 6 integrin, which is closely linked to periductal fibrogenesis. The findings provide a rationale for the use of inhibitors of alpha v beta 6 integrin or TGF beta for down-regulating fibrosis in the setting of acute or ongoing biliary injury.