Integrin αvβ6 is highly expressed on certain activated epithelia, where it mediates attachment to fibronectin and serves as coreceptor for the activation of latent transforming growth factor (TGF)-β1. Because its role in liver fibrosis is unknown, we studied αvβ6 function in vitro and explored the antifibrotic potential of the specific αvβ6 antagonist EMD527040.

Experimental liver fibrosis was studied in rats after bile duct ligation (BDL) and in Mdr2(abcb4)^−/− mice. Different doses of EMD527040 were given to rats from week 2 to 6 after BDL and to Mdr2^−/− mice from week 4 to 8. Liver collagen was quantified, and expression of αvβ6 and fibrosis-related transcripts was determined by quantitative reverse-transcription polymerase chain reaction. αvβ6-expressing cells, bile duct proliferation, and apoptosis were assessed histologically. The effect of EMD527040 on cholangiocyte adhesion, proliferation, apoptosis, and TGF-β1 activation was studied in vitro.

αvβ6 was highly expressed on proliferating bile duct epithelia in fibrosis, with 100-fold increased transcript levels in advanced fibrosis. EMD527040 attenuated bile ductular proliferation and peribiliary collagen deposition by 40%–50%, induced down-regulation of fibrogenic and up-regulation of fibrolytic genes, and improved liver architecture and function. In vitro αvβ6 inhibition reduced activated cholangiocyte proliferation, their adhesion to fibronectin, and endogenous activation of TGF-β1 by 50% but did not affect bile duct apoptosis.

Integrin αvβ6 is strongly up-regulated in proliferating bile duct epithelia and drives fibrogenesis via adhesion to fibronectin and auto/paracrine TGF-β1 activation. Pharmacologic inhibition of αvβ6 potently inhibits the progression of primary and secondary biliary fibrosis.