Knockout of the Tachykinin Receptor 1 in the Mdr2-/- (Abcb4-/-) Mouse Model of Primary Sclerosing Cholangitis Reduces Biliary Damage and Liver Fibrosis. Academic Article uri icon


  • 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-1 (TGF-1) biliary secretion. Recent evidence indicates a role for miR-31 (MIR31) in TGF-1-induced liver fibrosis. We aimed to define the role of the SP/NK1R/TGF-1/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. Invivo 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.

published proceedings

  • Am J Pathol

altmetric score

  • 4.2

author list (cited authors)

  • Ceci, L., Francis, H., Zhou, T., Giang, T., Yang, Z., Meng, F., ... Alpini, G.

citation count

  • 4

complete list of authors

  • 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

publication date

  • November 2020