Integrin αvβ6 is a marker of the progression of biliary and portal liver fibrosis and a novel target for antifibrotic therapies

Background/Aims: The integrin alpha v beta 6 promotes proliferation of specialized epithelia and acts as a receptor for the activation of latent TGF beta 1 We studied alpha v beta 6 expression in experimental and human liver fibrosis and the potential of its pharmacological inhibition for treatment of hepatic fibrosis. Methods: alpha v beta 6 expression was studied by quantitative PCR and immunohistochemistry in rats with cirrhosis due to bile duct ligation (BDL), administration of thioacetamide (TAA), in Mdr2(Abcb4)(-/-) mice with spontaneous biliary fibrosis, and in livers of patients with chronic hepatitis C (n = 79) and end-stage liver disease due to various etiologies (n = 18). The effect of a selective alpha v beta 6 inhibitor was evaluated in Mdr2(Abcb4)(-/-) mice with ongoing fibrogenesis. Results: Integrin 06 mRNA increased with fibrosis stage in hepatitis C and was upregulated between 25- and 100-fold in TAA- and BDL-induced cirrhosis, in Mdr2(Abcb4)(-/-) mice and in human end-stage liver disease. alpha v beta 6 protein was absent in normal livers and expressed de novo on (activated) bile duct epithelia and transitional hepatocytes. A single dose of the alpha v beta 6 inhibitor injected into Mdr2(Abcb4)(-/-) mice significantly induced profibrolytic matrix metalloproteinases (MMP)-8 and -9 after 3 h, with a corresponding increase in extracellular matrix-degrading activities. In parallel profibrogenic transcripts (procollagen alpha 1(I), TGF beta 2, and MMP-2) showed a trend of downregullation. Conclusions: (1) Integrin alpha v beta 6 is induced de, novo in rodent and human liver fibrosis, where it is expressed on activated bile duct epithelia and (transitional) hepatocytes during fibrosis progression. (2) In vivo a single dose of a small molecule alpha v beta 6 inhibitor induced antifibrogenic and profibrolytic genes and activities, suggesting alpha v beta 6 is a unique target for treatment of liver fibrosis. (C) 2008 Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver.