Integrin alphavbeta6 is a marker of the progression of biliary and portal liver fibrosis and a novel target for antifibrotic therapies

J Hepatol. 2008 Mar;48(3):453-64. doi: 10.1016/j.jhep.2007.11.021. Epub 2008 Jan 14.

Abstract

Background/aims: The integrin alphavbeta6 promotes proliferation of specialized epithelia and acts as a receptor for the activation of latent TGFbeta1. We studied alphavbeta6 expression in experimental and human liver fibrosis and the potential of its pharmacological inhibition for treatment of hepatic fibrosis.

Methods: alphavbeta6 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 alphavbeta6 inhibitor was evaluated in Mdr2(Abcb4)(-/-) mice with ongoing fibrogenesis.

Results: Integrin beta6 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. alphavbeta6 protein was absent in normal livers and expressed de novo on (activated) bile duct epithelia and transitional hepatocytes. A single dose of the alphavbeta6 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 alpha1(I), TGFbeta2, and MMP-2) showed a trend of downregulation.

Conclusions: (1) Integrin alphavbeta6 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 alphavbeta6 inhibitor induced antifibrogenic and profibrolytic genes and activities, suggesting alphavbeta6 is a unique target for treatment of liver fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • ATP-Binding Cassette Sub-Family B Member 4
  • Adult
  • Animals
  • Antigens, Neoplasm / metabolism*
  • Bile Ducts / drug effects
  • Bile Ducts / metabolism
  • Bile Ducts / pathology
  • Biomarkers / metabolism
  • Biopsy
  • Disease Models, Animal
  • Disease Progression
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Female
  • Hepatitis C, Chronic / metabolism
  • Hepatitis C, Chronic / pathology
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Humans
  • Integrins / metabolism*
  • Liver / drug effects
  • Liver / metabolism*
  • Liver / pathology
  • Liver Cirrhosis / drug therapy*
  • Liver Cirrhosis / metabolism*
  • Male
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Pyridines / pharmacology
  • Pyridines / therapeutic use
  • Rats
  • Rats, Wistar

Substances

  • ATP Binding Cassette Transporter, Subfamily B
  • Antigens, Neoplasm
  • Biomarkers
  • EMD 527040
  • Integrins
  • Pyridines
  • integrin alphavbeta6