title: Divergent Inflammatory, Fibrogenic, and Liver Progenitor Cell Dynamics in Two Common Mouse Models of Chronic Liver Injury.
abstract: Complications of end-stage chronic liver disease signify a major cause of mortality worldwide. Irrespective of the underlying cause, most chronic liver diseases are characterized by hepatocellular necrosis, inflammation, fibrosis, and proliferation of liver progenitor cells or ductular reactions. Vast differences exist between experimental models that mimic these processes, and their identification is fundamental for translational research. We compared two common murine models of chronic liver disease: the choline-deficient, ethionine-supplemented (CDE) diet versus thioacetamide (TAA) supplementation. Markers of liver injury, including serum alanine transaminase levels, apoptosis, hepatic fat loading, and oxidative stress, as well as inflammatory, fibrogenic and liver progenitor cell responses, were assessed at days 3, 7, 14, 21, and 42. This study revealed remarkable differences between the models. It identified periportal injury and fibrosis with an early peak and slow normalization of all parameters in the CDE regimen, whereas TAA-treated mice had pericentral patterns of progressive injury and fibrosis, resulting in a more severe hepatic injury phenotype. This study is the first to resolve two different patterns of injury and fibrosis in the CDE and TAA model and to indisputably identify the fibrosis pattern in the TAA model as driven from the pericentral vein region. Our data provide a valuable foundation for future work using the CDE and TAA regimens to model a variety of human chronic liver diseases.
authors.affiliation: School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Bentley, Western Australia, Australia.
authors.forename: Julia
authors.initials: J
authors.lastname: Köhn-Gaone
authors.affiliation: School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Bentley, Western Australia, Australia.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Dwyer
authors.affiliation: Centenary Institute of Cancer Medicine and Cell Biology, Camperdown, New South Wales, Australia.
authors.forename: Candice A
authors.initials: CA
authors.lastname: Grzelak
authors.affiliation: Faculty of Medicine and Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Gregory
authors.initials: G
authors.lastname: Miller
authors.affiliation: Centenary Institute of Cancer Medicine and Cell Biology, Camperdown, New South Wales, Australia; Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Shackel
authors.affiliation: Faculty of Medicine and Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia; QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Grant A
authors.initials: GA
authors.lastname: Ramm
authors.affiliation: Centenary Institute of Cancer Medicine and Cell Biology, Camperdown, New South Wales, Australia; Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia; A.W. Morrow Gastroenterology and Liver Centre, Sydney, New South Wales, Australia.
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: McCaughan
authors.affiliation: School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Bentley, Western Australia, Australia; School of Chemistry and Biochemistry, University of Western Australia, Crawley, Western Australia, Australia.
authors.forename: Caryn L
authors.initials: CL
authors.lastname: Elsegood
authors.affiliation: School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Bentley, Western Australia, Australia; Fremantle and Fiona Stanley Hospitals, Murdoch, Western Australia, Australia; School of Veterinary and Life Sciences, Murdoch University, Murdoch, Western Australia, Australia.
authors.forename: John K
authors.initials: JK
authors.lastname: Olynyk
authors.affiliation: School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Bentley, Western Australia, Australia; School of Medicine and Pharmacology, University of Western Australia, Fremantle, Western Australia, Australia. Electronic address: n.tirnitz-parker@curtin.edu.au.
authors.forename: Janina E E
authors.initials: JEE
authors.lastname: Tirnitz-Parker
mesh_terms: D000818:Animals; D002908:Chronic Disease; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000473:pathology / Q000502:physiology*; D007150:Immunohistochemistry; D008107:Liver Diseases / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D060888:Real-Time Polymerase Chain Reaction; D013234:Stem Cells / Q000473:pathology / Q000502:physiology*