A new xenobiotic-induced mouse model of sclerosing cholangitis and biliary fibrosis
A new xenobiotic-induced mouse model of sclerosing cholangitis and biliary fibrosis
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DOI：
10.2353/ajpath.2007.061133
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发表时间：
2007-08-01
影响因子：
6
通讯作者：
Trauner, Michael
中科院分区：
文献类型：
--
作者：
Fickert, Peter;Stoeger, Ulrike;Trauner, Michael
异生素和药物可能导致胆管病和胆道纤维化，但其潜在机制尚不清楚。因此，我们的目的是表征 3,5-二乙氧基羰基-1,4-二氢可力丁 (DDC) 喂养小鼠的肝胆损伤和胆道纤维化的原因和后果，作为异生素诱导的胆管病的新模型。在 DDC 和对照饮食喂养的瑞士白化小鼠中纵向研究肝脏形态、炎症标志物、细胞增殖、纤维化、胆汁形成、胆卟啉分泌和肝胆转运蛋白表达。 DDC喂养导致胆道卟啉分泌增加，并诱导胆管上皮细胞中血管细胞粘附分子、骨桥蛋白和肿瘤坏死因子-a的表达。这与明显的胆管周炎相关，伴有 CD11b 阳性细胞数量显着增加、导管反应和导管周肌成纤维细胞活化，导致大导管疾病和胆道型肝纤维化。 4周后，我们不断观察导管内卟啉色素栓。谷胱甘肽和磷脂的排泄随着时间的推移显着减少。 Ntcp、Oatp4和Mrp2的表达显着降低，而Bsep表达保持不变，适应性MrP3和Mrp4表达显着诱导。我们证明，给小鼠喂食 DDC 会导致 i) 胆管细胞反应表型和胆管损伤，i!) 胆管周炎、导管周围纤维化、导管反应，以及随后的门脉桥接，iii) Mrp2 下调和谷胱甘肽排泄受损，以及 iv) 节段性胆管梗阻。该模型对于研究异生素诱导的慢性胆管病及其后遗症（包括胆道纤维化）的机制可能有价值。
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 dietfed Swiss albino mice. DDC feeding led to increased biliary porphyrin secretion and induction of vascular cell adhesion molecule, osteopontin, and tumor necrosis factor-a 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, i!) 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.