Activation of the secretin (Sct)/secretin receptor (SR) axis stimulates ductular reaction and liver fibrosis that 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 to BDL wild-type (WT) 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 to BDL WT 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.

The secretin/secretin receptor axis modulates ductular reaction and liver fibrosis through changes in transforming growth factor (TGF)-β1-mediated biliary senescence / Wu, Nan; Meng, Fanyin; Zhou, Tianhao; Venter, Julie; Giang, Thao K; Kyritsi, Konstantina; Wu, Chaodong; Alvaro, Domenico; Onori, Paolo; Mancinelli, Romina; Gaudio, Eugenio; Francis, Heather; Alpini, Gianfranco; Glaser, Shannon; Franchitto, Antonio. - In: THE AMERICAN JOURNAL OF PATHOLOGY. - ISSN 0002-9440. - STAMPA. - 188:10(2018), pp. 2264-2280. [10.1016/j.ajpath.2018.06.015]

The secretin/secretin receptor axis modulates ductular reaction and liver fibrosis through changes in transforming growth factor (TGF)-β1-mediated biliary senescence

Alvaro, Domenico;Onori, Paolo;Mancinelli, Romina;Gaudio, Eugenio;Franchitto, Antonio
2018

Abstract

Activation of the secretin (Sct)/secretin receptor (SR) axis stimulates ductular reaction and liver fibrosis that 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 to BDL wild-type (WT) 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 to BDL WT 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.
2018
secretin/secretin receptor axis; TGFβ1; biliary senescence; liver fibrosis
01 Pubblicazione su rivista::01a Articolo in rivista
The secretin/secretin receptor axis modulates ductular reaction and liver fibrosis through changes in transforming growth factor (TGF)-β1-mediated biliary senescence / Wu, Nan; Meng, Fanyin; Zhou, Tianhao; Venter, Julie; Giang, Thao K; Kyritsi, Konstantina; Wu, Chaodong; Alvaro, Domenico; Onori, Paolo; Mancinelli, Romina; Gaudio, Eugenio; Francis, Heather; Alpini, Gianfranco; Glaser, Shannon; Franchitto, Antonio. - In: THE AMERICAN JOURNAL OF PATHOLOGY. - ISSN 0002-9440. - STAMPA. - 188:10(2018), pp. 2264-2280. [10.1016/j.ajpath.2018.06.015]
File allegati a questo prodotto
File Dimensione Formato  
Wu_Secretin/secretin_2017.pdf

solo gestori archivio

Tipologia: Versione editoriale (versione pubblicata con il layout dell'editore)
Licenza: Tutti i diritti riservati (All rights reserved)
Dimensione 6.96 MB
Formato Unknown
6.96 MB Unknown   Contatta l'autore

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1133958
Citazioni
  • ???jsp.display-item.citation.pmc??? 15
  • Scopus 32
  • ???jsp.display-item.citation.isi??? 28
social impact