Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Reiter, F.
Development of Sclerosing Cholangitis in Mdr2 (Abcb4) Knockout Mice- A Longitudinal Study in Aging Mice
[ Diplomarbeit ] Medical University of Graz; 2010. pp. 72
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Fickert Peter
- Trauner Michael
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- Abstract:
- Background and Aims: Primary sclerosing cholangitis (PSC) represents a chronic cholestatic liver disease frequently leading to liver cirrhosis and the need for liver-transplantation. Despite intensive research on the pathogenesis of PSC it is still widely unknown. Disruption of the Mdr2 (Abcb4) gene results in a mouse model which displays histological features of human PSC such as onion skin like periductal fibrosis and liver fibrosis of the biliary type. After delivery and starting suckling Mdr2 (-/-) mice develop severe inflammation and fibrosis of the liver, which can lead to a hepatocellular carcinoma in elder mice. To date little is known on the time course of inflammation and fibrosis as well as gender specific differences. Furthermore it is important to clarify if Mdr2 (-/-) mice develop liver cirrhosis, which can often be seen in patients suffering from PSC but could yet not be observed in rodent models. Material and Methods: Frozen liver tissue of Mdr2 (-/-) mice (obtained from the Jackson Laboratory, Bar Harbor, MA) was arranged retrospectively in six groups out of a period ranging from 6 to 13 months: 6 to 7 months; 9 to 10 months; 11 to 13 months. Development and potential gender differences in liver function, histological phenotype, fibrosis, inflammation as well as ductular proliferation were examined by analyzing serum biochemistry, H&E staining, Sirius red staining, real-time PCR, immuno-histochemistry and Western blot. Results: Mdr2 (-/-) mice did not develop biliary cirrhosis, while the characteristic histological pattern of cholestatic liver disease was found. Significant differences in hydroxyproline content, CK19 mRNA expression between male and female animals (6-7 month old groups), as well as differences in F4/80 and IL-1ß mRNA expression levels between 9 to 10 month-old groups, were detected in this study. We found no gender or age specific differences in regard to liver function, expression of genes and proteins relevant for inflammation, fibrosis, ductular and hepatocellular proliferation were observed. Conclusion: In young mice hepatic inflammation and fibrosis were more pronounced in female mice. However the extent of liver damage in males aligned itself a later point. Neither male nor female mice showed progression to liver cirrhosis. Future studies should determine potential factors leading to stabilization of the cholestatic phenotype in Mdr2 (-/-) mice since such mechanisms could unravel potential future therapeutic targets.