A new xenobiotic-induced mouse model of sclerosing cholangitis and biliary fibrosis.
Xenobiotics and drugs may lead to cholangiopathies and biliary fibrosis, but the underlying mechanisms are largely unknown. Therefore, we aimed to characterize the cause and consequences of hepatobiliary injury and biliary fibrosis in 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-fed mice as a novel model of xenobiotic-induced cholangiopathy. Liver morphology, markers of inflammation, cell proliferation, fibrosis, bile formation, biliary porphyrin secretion, and hepatobiliary transporter expression were studied longitudinally in DDC- and control diet-fed Swiss albino mice. DDC feeding led to increased biliary porphyrin secretion and induction of vascular cell adhesion molecule, osteopontin, and tumor necrosis factor-alpha expression in bile duct epithelial cells. This was associated with a pronounced pericholangitis with a significantly increased number of CD11b-positive cells, ductular reaction, and activation of periductal myofibroblasts, leading to large duct disease and a biliary type of liver fibrosis. After 4 weeks, we constantly observed intraductal porphyrin pigment plugs. Glutathione and phospholipid excretion significantly decreased over time. Expression of Ntcp, Oatp4, and Mrp2 was significantly reduced, whereas Bsep expression remained unchanged and adaptive Mrp3 and Mrp4 expression was significantly induced. We demonstrate that DDC feeding in mice leads to i) a reactive phenotype of cholangiocytes and bile duct injury, ii) pericholangitis, periductal fibrosis, ductular reaction, and consequently portal-portal bridging, iii) down-regulation of Mrp2 and impaired glutathione excretion, and iv) segmental bile duct obstruction. This model may be valuable to investigate the mechanisms of xenobiotic-induced chronic cholangiopathies and its sequels including biliary fibrosis.
Fickert
Peter
P
Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Medicine, Medical University Graz, Austria.
Stöger
Ulrike
U
Fuchsbichler
Andrea
A
Moustafa
Tarek
T
Marschall
Hanns-Ulrich
HU
Weiglein
Andreas H
AH
Tsybrovskyy
Oleksiy
O
Jaeschke
Hartmut
H
Zatloukal
Kurt
K
Denk
Helmut
H
Trauner
Michael
M
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D001652:Bile Ducts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015209:Cholangitis, Sclerosing / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D003997:Dicarbethoxydihydrocollidine / Q000008:administration & dosage / Q000633:toxicity*; D004195:Disease Models, Animal; D005978:Glutathione / Q000378:metabolism; D006909:Hydroxyproline / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008105:Liver Cirrhosis, Biliary / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008954:Models, Biological; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D053495:Osteopontin / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D015262:Xenobiotics / Q000008:administration & dosage / Q000633:toxicity*
D001647:Bile Acids and Salts; D002784:Cholesterol; D003997:Dicarbethoxydihydrocollidine; D005978:Glutathione; D006909:Hydroxyproline; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D053495:Osteopontin; D010743:Phospholipids; D014409:Tumor Necrosis Factor-alpha; D015262:Xenobiotics; C114462:multidrug resistance-associated protein 3