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.

Knockout of the tachykinin receptor 1 in the Mdr2−/− (Abcb4−/−) mouse model of primary sclerosing cholangitis reduces biliary damage and liver fibrosis / Ceci, L.; Francis, H.; Zhou, T.; Giang, T.; Yang, Z.; Meng, F.; Wu, N.; Kennedy, L.; Kyritsi, K.; Meadows, V.; Wu, C.; Liangpunsakul, S.; Franchitto, A.; Sybenga, A.; Ekser, B.; Mancinelli, R.; Onori, P.; Gaudio, E.; Glaser, S.; Alpini, G.. - In: THE AMERICAN JOURNAL OF PATHOLOGY. - ISSN 0002-9440. - 190:11(2020), pp. 2251-2266. [10.1016/j.ajpath.2020.07.007]

Knockout of the tachykinin receptor 1 in the Mdr2−/− (Abcb4−/−) mouse model of primary sclerosing cholangitis reduces biliary damage and liver fibrosis

Ceci L.;Franchitto A.;Mancinelli R.;Onori P.;Gaudio E.;
2020

Abstract

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.
2020
ATP binding cassette transporter; subfamily B; animals; disease models; gene knockdown techniques; mice; knockout; receptors; neurokinin-1; bile ducts; cholangitis; sclerosing; liver cirrhosis
01 Pubblicazione su rivista::01a Articolo in rivista
Knockout of the tachykinin receptor 1 in the Mdr2−/− (Abcb4−/−) mouse model of primary sclerosing cholangitis reduces biliary damage and liver fibrosis / Ceci, L.; Francis, H.; Zhou, T.; Giang, T.; Yang, Z.; Meng, F.; Wu, N.; Kennedy, L.; Kyritsi, K.; Meadows, V.; Wu, C.; Liangpunsakul, S.; Franchitto, A.; Sybenga, A.; Ekser, B.; Mancinelli, R.; Onori, P.; Gaudio, E.; Glaser, S.; Alpini, G.. - In: THE AMERICAN JOURNAL OF PATHOLOGY. - ISSN 0002-9440. - 190:11(2020), pp. 2251-2266. [10.1016/j.ajpath.2020.07.007]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1469730
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