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

Published:January 14, 2008DOI:https://doi.org/10.1016/j.jhep.2007.11.021

      Background/Aims

      The integrin αvβ6 promotes proliferation of specialized epithelia and acts as a receptor for the activation of latent TGFβ1. We studied αvβ6 expression in experimental and human liver fibrosis and the potential of its pharmacological inhibition for treatment of hepatic fibrosis.

      Methods

      αvβ6 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 αvβ6 inhibitor was evaluated in Mdr2(Abcb4)−/− mice with ongoing fibrogenesis.

      Results

      Integrin β6 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. αvβ6 protein was absent in normal livers and expressed de novo on (activated) bile duct epithelia and transitional hepatocytes. A single dose of the αvβ6 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 α1(I), TGFβ2, and MMP-2) showed a trend of downregulation.

      Conclusions

      (1) Integrin αvβ6 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 αvβ6 inhibitor induced antifibrogenic and profibrolytic genes and activities, suggesting αvβ6 is a unique target for treatment of liver fibrosis.

      Keywords

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