Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Stoeger, U.
Molecular machanisms of cholestasis in a mouse model of chemical induced bile duct injury
[ Dissertation ] Medical University of Graz; 2006. pp.
- Autor*innen der Med Uni Graz:
- Leb-Stöger Ulrike
- Betreuer*innen:
- Fickert Peter
- Trauner Michael
- Altmetrics:
- Abstract:
- Chronic cholestasis represents an important couse of biliary fibrosis and cirrhosis. We aimed to characterize hepatobiliary injury and biliary fibrosis in a mouse model of xenobiotic-induced cholangiopahty. Therefore liver morphology, markers of inflammation, proliferation, fibrosis, bile formation and hepatobiliary transporter espression were studied in control diet-fed and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-fed Swiss albino mice (0,1/ w/w, for 1,4 and 8 weeks). DDC feeding led to induction of VCAM, osteopontin, and TNF- expression in bile duct epithelial cells. This was paralleled by a pronounced percholangitis with significantly increased number of CD11-positive cells, ductular proliferation and proliferation of perductal myofibroblasts leading to a biliary type of fibrosis (hepatic hydroxyproline content 23973 vs. 9216 g liver in controls, p<0,05). After 4 weeks intraductal porphyrin plugs were found on bile duct plastination studies. Glutathione excretion decreased significantly over time whereas phopholipid and bile acid excretion remained unchanged. Expression of Ntcp. Oatp1, and Mrp2 was significantly reduced while Bsep expression was preserved and adaptive Mrp3 and Mrp4 expression was significantly induced. We conclude that DDC-feeding in mice leads to (i) bile duct injury with a reactive phenotype of cholangiocytes, (ii) percholangitis, periductal fibrosis, ductular proliferation, and portal-portal bridging fibrosis, (iii) impaired glutathione excretion due to downregulation of Mrp2 and (iv) segmental bile duct obstruction. This model may be instrumental to study the mechanisms of xenobiotic-induced chronic cholangitis and its sequelae, including biliary fibrosis.