Browsing by Subject "Bile ducts"

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    Amelioration of Large Bile Duct Damage by Histamine-2 Receptor Vivo-Morpholino Treatment
    (Elsevier, 2020-05) Kennedy, Lindsey; Meadows, Vik; Kyritsi, Konstantina; Pham, Linh; Kundu, Debjyoti; Kulkarni, Rewa; Cerritos, Karla; Demieville, Jennifer; Hargrove, Laura; Glaser, Shannon; Zhou, Tianhao; Jaeger, Victoria; Alpini, Gianfranco; Francis, Heather; Medicine, School of Medicine
    Histamine binds to one of the four G-protein-coupled receptors expressed by large cholangiocytes and increases large cholangiocyte proliferation via histamine-2 receptor (H2HR), which is increased in patients with primary sclerosing cholangitis (PSC). Ranitidine decreases liver damage in Mdr2-/- (ATP binding cassette subfamily B member 4 null) mice. We targeted hepatic H2HR in Mdr2-/- mice using vivo-morpholino. Wild-type and Mdr2-/- mice were treated with mismatch or H2HR vivo-morpholino by tail vein injection for 1 week. Liver damage, mast cell (MC) activation, biliary H2HR, and histamine serum levels were studied. MC markers were determined by quantitative real-time PCR for chymase and c-kit. Intrahepatic biliary mass was detected by cytokeratin-19 and F4/80 to evaluate inflammation. Biliary senescence was determined by immunofluorescence and senescence-associated β-galactosidase staining. Hepatic fibrosis was evaluated by staining for desmin, Sirius Red/Fast Green, and vimentin. Immunofluorescence for transforming growth factor-β1, vascular endothelial growth factor-A/C, and cAMP/ERK expression was performed. Transforming growth factor-β1 and vascular endothelial growth factor-A secretion was measured in serum and/or cholangiocyte supernatant. Treatment with H2HR vivo-morpholino in Mdr2-/--mice decreased hepatic damage; H2HR protein expression and MC presence or activation; large intrahepatic bile duct mass, inflammation and senescence; and fibrosis, angiogenesis, and cAMP/phospho-ERK expression. Inhibition of H2HR signaling ameliorates large ductal PSC-induced damage. The H2HR axis may be targeted in treating PSC.
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    Knockout of the Tachykinin Receptor 1 in the Mdr2−/− (Abcb4−/−) Mouse Model of Primary Sclerosing Cholangitis Reduces Biliary Damage and Liver Fibrosis
    (Elsevier, 2020-11) Ceci, Ludovica; Francis, Heather; Zhou, Tianhao; Giang, Thao; Yang, Zhihong; Meng, Fanyin; Wu, Nan; Kennedy, Lindsey; Kyritsi, Konstantina; Meadows, Vik; Wu, Chaodong; Liangpunsakul, Suthat; Franchitto, Antonio; Sybenga, Amelia; Ekser, Burcin; Mancinelli, Romina; Onori, Paolo; Gaudio, Eugenio; Glaser, Shannon; Alpini, Gianfranco; Medicine, School of Medicine
    Activation of the substance P (SP)/neurokinin 1 receptor (NK1R) axis triggers biliary damage/senescence and liver fibrosis in bile duct ligated and Mdr2-/- (alias Abcb4-/-) mice through enhanced transforming growth factor-β1 (TGF-β1) biliary secretion. Recent evidence indicates a role for miR-31 (MIR31) in TGF-β1-induced liver fibrosis. We aimed to define the role of the SP/NK1R/TGF-β1/miR-31 axis in regulating biliary proliferation and liver fibrosis during cholestasis. Thus, we generated a novel model with double knockout of Mdr2-/- and NK1R-/ (alias Tacr1-/-) to further address the role of the SP/NK1R axis during chronic cholestasis. In vivo studies were performed in the following 12-week-old male mice: (i) NK1R-/-; (ii) Mdr2-/-; and (iii) NK1R-/-/Mdr2-/- (Tacr1-/-/Abcb4-/-) and their corresponding wild-type controls. Liver tissues and cholangiocytes were collected, and liver damage, changes in biliary mass/senescence, and inflammation as well as liver fibrosis were evaluated by both immunohistochemistry in liver sections and real-time PCR. miR-31 expression was measured by real-time PCR in isolated cholangiocytes. Decreased ductular reaction, liver fibrosis, biliary senescence, and biliary inflammation were observed in NK1R-/-/Mdr2-/- mice compared with Mdr2-/- mice. Elevated expression of miR-31 was observed in Mdr2-/- mice, which was reduced in NK1R-/-/Mdr2-/- mice. Targeting the SP/NK1R and/or miR-31 may be a potential approach in treating human cholangiopathies, including primary sclerosing cholangitis.
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    Nrf2 deficiency causes hepatocyte dedifferentiation and reduced albumin production in an experimental extrahepatic cholestasis model
    (PLOS, 2022-06-13) Wang, Guo-Ying; Garcia, Veronica; Lee, Joonyong; Yanum, Jennifer; Lin, Jingmei; Jiang, Huaizhou; Dai, Guoli; Biology, School of Science
    The transcription factor Nrf2 modulates the initiation and progression of a number of diseases including liver disorders. We evaluated whether Nrf2 mediates hepatic adaptive responses to cholestasis. Wild-type and Nrf2-null mice were subjected to bile duct ligation (BDL) or a sham operation. As cholestasis progressed to day 15 post-BDL, hepatocytes in the wild-type mice exhibited a tendency to dedifferentiate, indicated by the very weak expression of hepatic progenitor markers: CD133 and tumor necrosis factor-like weak induced apoptosis receptor (Fn14). During the same period, Nrf2 deficiency augmented this tendency, manifested by higher CD133 expression, earlier, stronger, and continuous induction of Fn14 expression, and markedly reduced albumin production. Remarkably, as cholestasis advanced to the late stage (40 days after BDL), hepatocytes in the wild-type mice exhibited a Fn14+ phenotype and strikingly upregulated the expression of deleted in malignant brain tumor 1 (DMBT1), a protein essential for epithelial differentiation during development. In contrast, at this stage, hepatocytes in the Nrf2-null mice entirely inhibited the upregulation of DMBT1 expression, displayed a strong CD133+/Fn14+ phenotype indicative of severe dedifferentiation, and persistently reduced albumin production. We revealed that Nrf2 maintains hepatocytes in the differentiated state potentially via the increased activity of the Nrf2/DMBT1 pathway during cholestasis.