title: Mdr2 (Abcb4)-/- mice spontaneously develop severe biliary fibrosis via massive dysregulation of pro- and antifibrogenic genes.
abstract: OBJECTIVE
  Mdr2 (Abcb4)-/- mice develop hepatic lesions resembling primary sclerosing cholangitis. Our aim was to characterize the evolution of fibrosis in Mdr2-/- mice.
  
  
  METHODS
  Mdr2-/-mice and their wild-type littermates were sacrificed at 2, 4 and 8 weeks after birth. Hepatic collagen was determined biochemically. Fibrosis related transcript levels were quantified from livers by real-time RT-PCR, and MMP activities determined by substrate assays. Liver histology was assessed by connective tissue staining and immunohistochemistry for alpha-smooth muscle actin (alpha-SMA).
  
  
  RESULTS
  Mdr2-/- mice demonstrated a time-dependent increase of relative and total hepatic collagen (fivefold at 8 weeks, compared to wildtype controls), and maximal alpha-SMA immunoreactivity at 4 weeks. Compared to wildtype controls profibrogenic mRNA levels for procollagen alpha1(I), TGFbeta1, TGFbeta2, MMP-2 and -13, TIMP-1, PDGFbeta receptor, and PAI-1 were upregulated up to 27-fold. Most transcripts peaked at 4 weeks, but procollagen alpha1(I) mRNA increased steadily, TIMP-1 mRNA was constantly elevated (20-fold), MMP-13 mRNA was suppressed and interstitial collagenase and gelatinase activities were downregulated.
  
  
  CONCLUSIONS
  Mdr2-/- mice spontaneously progress to severe biliary fibrosis. This is due to a characteristic temporal pattern of upregulated profibrogenic and downregulated fibrolytic genes and activities. These mice are an attractive model to test potential antifibrotics for the treatment of (biliary) liver fibrosis.
authors.affiliation: Laboratory of Liver Research, Department of Medicine I, University of Erlangen-Nuremberg, Germany; Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Yury
authors.initials: Y
authors.lastname: Popov
authors.forename: Eleonora
authors.initials: E
authors.lastname: Patsenker
authors.forename: Peter
authors.initials: P
authors.lastname: Fickert
authors.forename: Michael
authors.initials: M
authors.lastname: Trauner
authors.forename: Detlef
authors.initials: D
authors.lastname: Schuppan
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics*; D000818:Animals; D001653:Bile Ducts, Intrahepatic / Q000473:pathology*; D004195:Disease Models, Animal; D008103:Liver Cirrhosis / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000097202:ATP-Binding Cassette Sub-Family B Member 4