title: Hepatitis C virus (HCV) protein expression enhances hepatic fibrosis in HCV transgenic mice exposed to a fibrogenic agent.
abstract: OBJECTIVE
  During chronic HCV infection, activation of fibrogenesis appears to be principally related to local inflammation. However, the direct role of hepatic HCV protein expression in fibrogenesis remains unknown.
  
  
  METHODS
  We used transgenic mice expressing the full length HCV open reading frame exposed to a 'second hit' of the fibrogenic agent carbon tetrachloride (CCl(4)). Both acute and chronic liver injuries were induced in these mice by CCl(4) injections. Liver injury, expression of matrix re-modeling genes, reactive oxygen species (ROS), inflammation, hepatocyte proliferation, ductular reaction and hepatic progenitor cells (HPC) expansion were examined.
  
  
  RESULTS
  After CCl(4) treatment, HCV transgenic mice exhibited enhanced liver fibrosis, significant changes in matrix re-modeling genes and increased ROS production compared to wild type littermates despite no differences in the degree of local inflammation. This increase was accompanied by a decrease in hepatocyte proliferation, which appeared to be due to delayed hepatocyte entry into the S phase. A prominent ductular reaction and hepatic progenitor cell compartment expansion were observed in transgenic animals. These observations closely mirror those previously made in HCV-infected individuals.
  
  
  CONCLUSIONS
  Together, these results demonstrate that expression of the HCV proteins in hepatocytes contributes to the development of hepatic fibrosis in the presence of other fibrogenic agents. In the presence of CCl(4), HCV transgenic mice display an intra-hepatic re-organization of several key cellular actors in the fibrogenic process.
authors.affiliation: Inserm U955, Créteil, France; Université Paris-Est, Créteil, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Chouteau
authors.forename: Nicole
authors.initials: N
authors.lastname: Defer
authors.forename: Alexandre
authors.initials: A
authors.lastname: Florimond
authors.forename: Julien
authors.initials: J
authors.lastname: Caldéraro
authors.forename: Martin
authors.initials: M
authors.lastname: Higgs
authors.forename: Aurore
authors.initials: A
authors.lastname: Gaudin
authors.forename: Emilie
authors.initials: E
authors.lastname: Mérour
authors.forename: Daniel
authors.initials: D
authors.lastname: Dhumeaux
authors.forename: Hervé
authors.initials: H
authors.lastname: Lerat
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Pawlotsky
mesh_terms: D000818:Animals; D001652:Bile Ducts / Q000378:metabolism; D002251:Carbon Tetrachloride; D049109:Cell Proliferation; D018946:Chemokine CCL5 / Q000378:metabolism; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D016174:Hepacivirus; D019698:Hepatitis C, Chronic / Q000150:complications / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism* / Q000502:physiology; D053539:Keratin-19 / Q000378:metabolism; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D053509:Matrix Metalloproteinase 13 / Q000235:genetics; D019278:Matrix Metalloproteinase 3 / Q000235:genetics; D020783:Matrix Metalloproteinase 7 / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D016366:Open Reading Frames; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018946:Chemokine CCL5; D053539:Keratin-19; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D019715:Tissue Inhibitor of Metalloproteinase-1; D014764:Viral Proteins; D002251:Carbon Tetrachloride; D053509:Matrix Metalloproteinase 13; D019278:Matrix Metalloproteinase 3; D020783:Matrix Metalloproteinase 7