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Am J Pathol. 2018 Oct;188(10):2264-2280. doi: 10.1016/j.ajpath.2018.06.015. Epub 2018 Jul 21.

The Secretin/Secretin Receptor Axis Modulates Ductular Reaction and Liver Fibrosis through Changes in Transforming Growth Factor-β1-Mediated Biliary Senescence.

Author information

1
Department of Medical Physiology, Department of Research, Texas A&M University College of Medicine, Temple, Texas.
2
Central Texas Veterans Health Care System, Temple, Texas; Baylor Scott & White Digestive Disease Research Center, Baylor Scott & White Health Care, Temple, Texas.
3
Department of Nutrition and Food Science, Texas A&M University, College Station, Texas.
4
Department of Gastroenterology, Sapienza, Rome, Italy.
5
Department of Anatomical, Histological, Forensic Medicine and Orthopaedics Sciences, Sapienza, Rome, Italy.
6
Department of Medical Physiology, Department of Research, Texas A&M University College of Medicine, Temple, Texas; Central Texas Veterans Health Care System, Temple, Texas; Baylor Scott & White Digestive Disease Research Center, Baylor Scott & White Health Care, Temple, Texas.
7
Department of Medical Physiology, Department of Research, Texas A&M University College of Medicine, Temple, Texas; Central Texas Veterans Health Care System, Temple, Texas; Baylor Scott & White Digestive Disease Research Center, Baylor Scott & White Health Care, Temple, Texas. Electronic address: galpini@medicine.tamhsc.edu.
8
Department of Anatomical, Histological, Forensic Medicine and Orthopaedics Sciences, Sapienza, Rome, Italy; Department of Medicine, Sapienza, Rome, Italy; Eleonora Lorillard Spencer Cenci Foundation, Rome, Italy.

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-/-, SR-/-, and Sct-/-/SR-/- bile duct ligated (BDL) mice compared with BDL wild-type mice. The reduction in hepatic fibrosis in Sct-/-, SR-/-, and Sct-/-/SR-/- 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.

PMID:
30036520
PMCID:
PMC6168967
DOI:
10.1016/j.ajpath.2018.06.015
[Indexed for MEDLINE]
Free PMC Article

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