Z Gastroenterol 2019; 57(01): e13
DOI: 10.1055/s-0038-1677072
1. Basic Hepatology (Fibrogenesis, NPC, Transport)
Georg Thieme Verlag KG Stuttgart · New York

A mouse model of chronic liver disease progression and acute-on-chronic liver failure

A Ghallab
1   Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany
6   Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt.
,
M Maiju
1   Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany
,
R Hassan
1   Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany
6   Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt.
,
A Zaza
1   Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany
,
U Hofmann
2   Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tübingen, Stuttgart, Germany.
,
EM Buhl
3   Institute of Pathology & Department of Nephrology, University Clinic of RWTH Aachen, Aachen, Germany.
,
KM Schneider
4   Department of Medicine III, University clinic RWTH Aachen, Aachen, Germany.
,
K Breuhahn
5   Institute of Pathology, University clinic Heidelberg, Heidelberg, Germany.
,
A Seddek
6   Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt.
,
C Trautwein
4   Department of Medicine III, University clinic RWTH Aachen, Aachen, Germany.
,
A Marx
7   Pathology institute, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
,
S Dooley
8   Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
,
T Longerich
5   Institute of Pathology, University clinic Heidelberg, Heidelberg, Germany.
,
P Boor
3   Institute of Pathology & Department of Nephrology, University Clinic of RWTH Aachen, Aachen, Germany.
,
D Drasdo
1   Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany
9   Institute National de Recherche en Informatique et en Automatique (INRIA), Le Chesnay, France.
,
JG Hengstler
1   Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
04 January 2019 (online)

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Acute-on-chronic liver failure (ACLF) is a common cause of death in patients with chronic liver disease (CLD), due to rapid decompensation and multi-organ failure. The mechanisms leading to ACLF are not fully understood. A major challenge is the lack of animal models that recapitulate CLD progression and ACLF similar to the human situation. To bridge this gap, we have established a mouse model of liver cirrhosis by long-term repeated carbon tetrachloride intoxication (CCl4, 1 g/kg, twice a week) up to one year. CLD progression was evaluated time-dependently every two months by biochemical, histopathological and immunohistochemical analyses, as well as by intravital imaging. Histopathological examination revealed centro-centro bridging fibrosis already after 2 months of repeated CCl4 administration. At 4 – 6 months, additionally architectural distortion was observed. At this stage (2 – 6 months), CYP450 enzymes and glutamine synthetase (GS) revealed centro-centro bridging pattern. Between 8 – 12 months, progression to cirrhosis with presence of regenerative and neoplastic nodules was present. This was accompanied by massive accumulation of extracellular matrix (ECM), infiltration of inflammatory macrophages, presence of a massive ductular reaction, capillarization of sinusoidal endothelial cells, loss of CYP450 and GS enzyme expression, and development of ascites. Furthermore, blood analyses revealed hyperammonemia, hypoglycemia, elevated urea, creatinine and bile salt concentrations. These changes are similar to those observed in patients with liver cirrhosis. To test the sensitivity of the mouse model to acute insults, mice at 12 months of repeated CCl4 intoxication or oil controls were acutely challenged with either acetaminophen (APAP), ethanol, bile duct ligation (BDL) or lipopolysaccharides (LPS). Cirrhotic livers showed decreased sensitivity to APAP and ethanol challenges, because of decreased CYP2E1 expression. Similarly, BDL induced less damage in the livers of the cirrhotic mice in comparison to the corresponding controls, which may be explained by adaptive changes in bile salt transporters. Interestingly, acute LPS challenge lead to more liver damage in the cirrhotic mice. In conclusion, a mouse model was established that recapitulates many features of CLD progression in human, including tissue remodeling, metabolic reprogramming and increased sensitivity to bacterial toxins.