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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.
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.
Affiliation
  • Ceci L; Division of Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, Indiana.
  • Francis H; Division of Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, Indiana; Richard L. Roudebush VA Medical Center, Indianapolis, Indiana.
  • Zhou T; Department of Medical Physiology, Texas A&M University, Bryan, Texas.
  • Giang T; Department of Medical Physiology, Texas A&M University, Bryan, Texas.
  • Yang Z; Division of Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, Indiana.
  • Meng F; Division of Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, Indiana; Richard L. Roudebush VA Medical Center, Indianapolis, Indiana.
  • Wu N; Division of Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, Indiana.
  • Kennedy L; Division of Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, Indiana.
  • Kyritsi K; Division of Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, Indiana.
  • Meadows V; Division of Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, Indiana.
  • Wu C; Department of Nutrition, Texas A&M University, College Station, Texas.
  • Liangpunsakul S; Division of Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, Indiana; Richard L. Roudebush VA Medical Center, Indianapolis, Indiana.
  • Franchitto A; Eleonora Lorillard Spencer Cenci Foundation, Rome, Italy.
  • Sybenga A; Department of Pathology and Laboratory Medicine, University of Vermont Medical Center, Burlington, Vermont.
  • Ekser B; Division of Transplant Surgery, Department of Surgery, Indiana University, Indianapolis, Indiana.
  • Mancinelli R; Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy.
  • Onori P; Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy.
  • Gaudio E; Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy.
  • Glaser S; Department of Medical Physiology, Texas A&M University, Bryan, Texas.
  • Alpini G; Division of Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, Indiana; Richard L. Roudebush VA Medical Center, Indianapolis, Indiana. Electronic address: galpini@iu.edu.
Am J Pathol ; 190(11): 2251-2266, 2020 11.
Article in En | MEDLINE | ID: mdl-32712019
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-ß1 (TGF-ß1) biliary secretion. Recent evidence indicates a role for miR-31 (MIR31) in TGF-ß1-induced liver fibrosis. We aimed to define the role of the SP/NK1R/TGF-ß1/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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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Bile Ducts / Cholangitis, Sclerosing / Receptors, Neurokinin-1 / ATP Binding Cassette Transporter, Subfamily B / Liver Cirrhosis Type of study: Prognostic_studies Limits: Animals Language: En Journal: Am J Pathol Year: 2020 Document type: Article Country of publication:
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Bile Ducts / Cholangitis, Sclerosing / Receptors, Neurokinin-1 / ATP Binding Cassette Transporter, Subfamily B / Liver Cirrhosis Type of study: Prognostic_studies Limits: Animals Language: En Journal: Am J Pathol Year: 2020 Document type: Article Country of publication: