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The Secretin/Secretin Receptor Axis Modulates Ductular Reaction and Liver Fibrosis through Changes in Transforming Growth Factor-β1-Mediated Biliary Senescence.
- Source :
-
The American journal of pathology [Am J Pathol] 2018 Oct; Vol. 188 (10), pp. 2264-2280. Date of Electronic Publication: 2018 Jul 21. - Publication Year :
- 2018
-
Abstract
- Activation of the secretin (Sct)/secretin receptor (SR) axis stimulates ductular reaction and liver fibrosis, which are hallmarks of cholangiopathies. Our aim was to define the role of Sct-regulated cellular senescence, and we demonstrated that both ductular reaction and liver fibrosis are significantly reduced in Sct <superscript>-/-</superscript> , SR <superscript>-/-</superscript> , and Sct <superscript>-/-</superscript> /SR <superscript>-/-</superscript> bile duct ligated (BDL) mice compared with BDL wild-type mice. The reduction in hepatic fibrosis in Sct <superscript>-/-</superscript> , SR <superscript>-/-</superscript> , and Sct <superscript>-/-</superscript> /SR <superscript>-/-</superscript> BDL mice was accompanied by reduced transforming growth factor-β1 levels in serum and cholangiocyte supernatant, as well as decreased expression of markers of cellular senescence in cholangiocytes in contrast to enhanced cellular senescence in hepatic stellate cells compared with BDL wild-type mice. Secretin directly stimulated the senescence of cholangiocytes and regulated, by a paracrine mechanism, the senescence of hepatic stellate cells and liver fibrosis via modulation of transforming growth factor-β1 biliary secretion. Targeting senescent cholangiocytes may represent a novel therapeutic approach for ameliorating hepatic fibrosis during cholestatic liver injury.<br /> (Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Bile Ducts cytology
Cellular Senescence physiology
Kupffer Cells metabolism
Male
Mice, Inbred C57BL
Mice, Knockout
Organ Size
RNA, Messenger metabolism
Secretin pharmacology
Liver Cirrhosis physiopathology
Receptors, G-Protein-Coupled physiology
Receptors, Gastrointestinal Hormone physiology
Secretin metabolism
Transforming Growth Factor beta1 physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1525-2191
- Volume :
- 188
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- The American journal of pathology
- Publication Type :
- Academic Journal
- Accession number :
- 30036520
- Full Text :
- https://doi.org/10.1016/j.ajpath.2018.06.015