title: Transcriptional basis for hepatic fibrosis in cystic fibrosis-associated liver disease.
abstract: OBJECTIVE
  Liver disease contributes to significant morbidity and mortality in cystic fibrosis (CF). Although all patients with CF express the defective CF transmembrane conductance regulator in cholangiocytes, many develop asymptomatic fibrosing liver disease. Only some develop cirrhosis, with pathogenesis remaining enigmatic. Available noninvasive diagnostic tools do not identify patients at risk before development of advanced fibrosis. We conducted a pilot study to identify genes associated with hepatic injury and fibrosis on liver biopsy that may help elucidate determinants of CF-associated liver disease (CFLD).
  
  
  METHODS
  Liver tissue from children with CFLD with various stages of hepatic fibrosis was compared with pediatric controls using cDNA array analysis. Differential expression of genes of interest was then assessed relative to pediatric control liver and non-CF cholestatic disease control liver from patients with biliary atresia, using both real-time reverse transcription-polymerase chain reaction and immunohistochemistry.
  
  
  RESULTS
  cDNA array demonstrated differential expression of numerous genes associated with hepatic fibrogenesis including collagens, matrix metalloproteinases, and chemokines in CFLD versus normal controls, particularly decreased expression in tissue remodeling genes including plasminogen activator inhibitor-1 (PAI-1, up to 25-fold) and tissue inhibitor of metalloproteinase-1 (TIMP-1); this was validated by real-time reverse transcription-polymerase chain reaction (PAI-1, P = 0.004; TIMP-1, P = 0.019). No significant decrease in PAI-1 or TIMP-1 mRNA was observed in biliary atresia versus normal control. Immunohistochemistry confirmed the decreased expression of hepatic PAI-1 and TIMP-1 protein in CFLD versus both normal and biliary atresia disease controls.
  
  
  CONCLUSIONS
  The coordinated differential expression of these genes associated with liver fibrosis provides evidence for a transcriptional basis for the pathogenesis of CFLD and provides avenues for further study. Clarifying the pathogenesis of CFLD will facilitate techniques for early, precirrhotic detection and targeted interventions.
authors.affiliation: The University of Queensland, Brisbane, Australia.
authors.forename: Tamara N
authors.initials: TN
authors.lastname: Pereira
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Lewindon
authors.forename: Ristan M
authors.initials: RM
authors.lastname: Greer
authors.forename: Anita C
authors.initials: AC
authors.lastname: Hoskins
authors.forename: Richard M
authors.initials: RM
authors.lastname: Williamson
authors.forename: Ross W
authors.initials: RW
authors.lastname: Shepherd
authors.forename: Grant A
authors.initials: GA
authors.lastname: Ramm
mesh_terms: D001656:Biliary Atresia / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D002648:Child; D002779:Cholestasis / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D003550:Cystic Fibrosis / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010865:Pilot Projects; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D018925:Chemokines; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D003094:Collagen; D020782:Matrix Metalloproteinases