title: Multiple inflammatory-, tissue remodelling- and fibrosis genes are differentially transcribed in the livers of Abcb4 (-/ - ) mice harbouring chronic cholangitis.
abstract: OBJECTIVE
  Abcb4 (-/-) mice secrete phosphatidylcholine-free, cytotoxic bile and develop chronic cholangitis. The aim of this study was to identify differentially transcribed genes whose products contribute to the liver tissue pathology during this disease.
  
  
  METHODS
  Hepatic gene transcription was measured in 3-, 6-, 9- and 20-week-old Abcb4 (-/-) mice (FVB.129P2-abcb4(tm1Bor)/J) using cDNA microarrays, with FVB/NJ Abcb4 (+/+) mice serving as controls. Focus was on inflammatory-, remodelling- and fibrosis genes. Marked differential transcription of inflammatory-, tissue remodelling- and fibrosis genes found by cDNA microarrays was verified by real-time polymerase chain reaction (PCR). Liver pathology was quantified by histopathology scoring.
  
  
  RESULTS
  Transcription of clade A3 Serpin genes showed early, marked down-regulation. The chemokine genes Ccl2, Ccl20 and Cxcl10 were markedly up-regulated. Tissue remodelling- and fibrosis genes exhibiting markedly up-regulated transcription included: Ctgf, Elf3, Lgals3, Mmp12, Mmp15, Spp1, Loxl2, Pdgfa, Pdgfrb, Sparc, Tgfb1, Tgfb2, Tgfbi, Tgfbr2 and Col1a1, Col1a2, Col2a1, Col3a1, Col4a1 genes. Microarray-based recordings of differential gene transcription of the majority of these genes harmonized with the liver histopathology score. Thus, cDNA microarray-based analysis showed increasing differential transcription of several inflammatory-, tissue remodelling- and fibrosis genes during the first 9 weeks of disease and a tendency towards differential transcription to stabilize at an elevated level from 9 to 20 weeks of disease.
  
  
  CONCLUSIONS
  Multiple genes regulating inflammation, tissue remodelling and fibrosis not previously linked to Abcb4 (-/-) cholangitis are identified as being differentially transcribed in Abcb4 (-/-) livers, where they contribute to the pathogenesis of liver tissue pathology.
authors.affiliation: Institute for Experimental Medical Research, Ullevål University Hospital and University of Oslo, Oslo, Norway. k.e.nakken@medisin.uio.no
authors.forename: Karl Esten
authors.initials: KE
authors.lastname: Nakken
authors.forename: Ståle
authors.initials: S
authors.lastname: Nygård
authors.forename: Terese
authors.initials: T
authors.lastname: Haaland
authors.forename: Knut Erik
authors.initials: KE
authors.lastname: Berge
authors.forename: Kristin
authors.initials: K
authors.lastname: Arnkvaern
authors.forename: Annlaug
authors.initials: A
authors.lastname: Ødegaard
authors.forename: Knut Jørgen
authors.initials: KJ
authors.lastname: Labori
authors.forename: Morten G
authors.initials: MG
authors.lastname: Raeder
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency* / Q000235:genetics*; D000818:Animals; D002761:Cholangitis / Q000235:genetics* / Q000503:physiopathology*; D002908:Chronic Disease; D005355:Fibrosis; D007249:Inflammation; D008099:Liver / Q000473:pathology / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics; D014158:Transcription, Genetic; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D012313:RNA; D000097202:ATP-Binding Cassette Sub-Family B Member 4