Substance P increases liver fibrosis by differential changes in senescence of cholangiocytes and hepatic stellate cells

Ying Wan, Fanyin Meng, Nan Wu, Tianhao Zhou, Julie Venter, Heather Francis, Lindsey Kennedy, Trenton Glaser, Francesca Bernuzzi, Pietro Invernizzi, Shannon Glaser, Qiaobing Huang, Gianfranco Alpini

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Abstract

Substance P (SP) is involved in the proliferation of cholangiocytes in bile duct–ligated (BDL) mice and human cholangiocarcinoma growth by interacting with the neurokinin-1 receptor (NK-1R). To identify whether SP regulates liver fibrosis during cholestasis, wild-type or NK-1R knockout (NK-1R–/–) mice that received BDL or sham surgery and multidrug resistance protein 2 knockout (Mdr2–/–) mice treated with either an NK-1R antagonist (L-733,060) or saline were used. Additionally, wild-type mice were treated with SP or saline intraperitoneally. In vivo, there was increased expression of tachykinin precursor 1 (coding SP) and NK-1R in both BDL and Mdr2–/– mice compared to wild-type mice. Expression of tachykinin precursor 1 and NK-1R was significantly higher in liver samples from primary sclerosing cholangitis patients compared to healthy controls. Knockout of NK-1R decreased BDL-induced liver fibrosis, and treatment with L-733,060 resulted in decreased liver fibrosis in Mdr2–/– mice, which was shown by decreased sirius red staining, fibrosis gene and protein expression, and reduced transforming growth factor-β1 levels in serum and cholangiocyte supernatants. Furthermore, we observed that reduced liver fibrosis in NK-1R–/– mice with BDL surgery or Mdr2–/– mice treated with L-733,060 was associated with enhanced cellular senescence of hepatic stellate cells and decreased senescence of cholangiocytes. In vitro, L-733,060 inhibited SP-induced expression of fibrotic genes in hepatic stellate cells and cholangiocytes; treatment with L-733,060 partially reversed the SP-induced decrease of senescence gene expression in cultured hepatic stellate cells and the SP-induced increase of senescence-related gene expression in cultured cholangiocytes. Conclusion: Collectively, our results demonstrate the regulatory effects of the SP/NK-1R axis on liver fibrosis through changes in cellular senescence during cholestatic liver injury. (Hepatology 2017;66:528–541).

Original languageEnglish (US)
Pages (from-to)528-541
Number of pages14
JournalHepatology
Volume66
Issue number2
DOIs
StatePublished - Aug 1 2017
Externally publishedYes

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Hepatic Stellate Cells
3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidine
Neurokinin-1 Receptors
Substance P
Liver Cirrhosis
Bile
Cell Aging
Gene Expression
Knockout Mice
Neurokinin-1 Receptor Antagonists
Sclerosing Cholangitis
Cholangiocarcinoma
Liver
Cholestasis
Transforming Growth Factors
Gastroenterology
Cultured Cells
Fibrosis
Staining and Labeling
Wounds and Injuries

ASJC Scopus subject areas

  • Hepatology

Cite this

Substance P increases liver fibrosis by differential changes in senescence of cholangiocytes and hepatic stellate cells. / Wan, Ying; Meng, Fanyin; Wu, Nan; Zhou, Tianhao; Venter, Julie; Francis, Heather; Kennedy, Lindsey; Glaser, Trenton; Bernuzzi, Francesca; Invernizzi, Pietro; Glaser, Shannon; Huang, Qiaobing; Alpini, Gianfranco.

In: Hepatology, Vol. 66, No. 2, 01.08.2017, p. 528-541.

Research output: Contribution to journalArticle

Wan, Y, Meng, F, Wu, N, Zhou, T, Venter, J, Francis, H, Kennedy, L, Glaser, T, Bernuzzi, F, Invernizzi, P, Glaser, S, Huang, Q & Alpini, G 2017, 'Substance P increases liver fibrosis by differential changes in senescence of cholangiocytes and hepatic stellate cells', Hepatology, vol. 66, no. 2, pp. 528-541. https://doi.org/10.1002/hep.29138
Wan, Ying ; Meng, Fanyin ; Wu, Nan ; Zhou, Tianhao ; Venter, Julie ; Francis, Heather ; Kennedy, Lindsey ; Glaser, Trenton ; Bernuzzi, Francesca ; Invernizzi, Pietro ; Glaser, Shannon ; Huang, Qiaobing ; Alpini, Gianfranco. / Substance P increases liver fibrosis by differential changes in senescence of cholangiocytes and hepatic stellate cells. In: Hepatology. 2017 ; Vol. 66, No. 2. pp. 528-541.
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abstract = "Substance P (SP) is involved in the proliferation of cholangiocytes in bile duct–ligated (BDL) mice and human cholangiocarcinoma growth by interacting with the neurokinin-1 receptor (NK-1R). To identify whether SP regulates liver fibrosis during cholestasis, wild-type or NK-1R knockout (NK-1R–/–) mice that received BDL or sham surgery and multidrug resistance protein 2 knockout (Mdr2–/–) mice treated with either an NK-1R antagonist (L-733,060) or saline were used. Additionally, wild-type mice were treated with SP or saline intraperitoneally. In vivo, there was increased expression of tachykinin precursor 1 (coding SP) and NK-1R in both BDL and Mdr2–/– mice compared to wild-type mice. Expression of tachykinin precursor 1 and NK-1R was significantly higher in liver samples from primary sclerosing cholangitis patients compared to healthy controls. Knockout of NK-1R decreased BDL-induced liver fibrosis, and treatment with L-733,060 resulted in decreased liver fibrosis in Mdr2–/– mice, which was shown by decreased sirius red staining, fibrosis gene and protein expression, and reduced transforming growth factor-β1 levels in serum and cholangiocyte supernatants. Furthermore, we observed that reduced liver fibrosis in NK-1R–/– mice with BDL surgery or Mdr2–/– mice treated with L-733,060 was associated with enhanced cellular senescence of hepatic stellate cells and decreased senescence of cholangiocytes. In vitro, L-733,060 inhibited SP-induced expression of fibrotic genes in hepatic stellate cells and cholangiocytes; treatment with L-733,060 partially reversed the SP-induced decrease of senescence gene expression in cultured hepatic stellate cells and the SP-induced increase of senescence-related gene expression in cultured cholangiocytes. Conclusion: Collectively, our results demonstrate the regulatory effects of the SP/NK-1R axis on liver fibrosis through changes in cellular senescence during cholestatic liver injury. (Hepatology 2017;66:528–541).",
author = "Ying Wan and Fanyin Meng and Nan Wu and Tianhao Zhou and Julie Venter and Heather Francis and Lindsey Kennedy and Trenton Glaser and Francesca Bernuzzi and Pietro Invernizzi and Shannon Glaser and Qiaobing Huang and Gianfranco Alpini",
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AU - Wan, Ying

AU - Meng, Fanyin

AU - Wu, Nan

AU - Zhou, Tianhao

AU - Venter, Julie

AU - Francis, Heather

AU - Kennedy, Lindsey

AU - Glaser, Trenton

AU - Bernuzzi, Francesca

AU - Invernizzi, Pietro

AU - Glaser, Shannon

AU - Huang, Qiaobing

AU - Alpini, Gianfranco

PY - 2017/8/1

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N2 - Substance P (SP) is involved in the proliferation of cholangiocytes in bile duct–ligated (BDL) mice and human cholangiocarcinoma growth by interacting with the neurokinin-1 receptor (NK-1R). To identify whether SP regulates liver fibrosis during cholestasis, wild-type or NK-1R knockout (NK-1R–/–) mice that received BDL or sham surgery and multidrug resistance protein 2 knockout (Mdr2–/–) mice treated with either an NK-1R antagonist (L-733,060) or saline were used. Additionally, wild-type mice were treated with SP or saline intraperitoneally. In vivo, there was increased expression of tachykinin precursor 1 (coding SP) and NK-1R in both BDL and Mdr2–/– mice compared to wild-type mice. Expression of tachykinin precursor 1 and NK-1R was significantly higher in liver samples from primary sclerosing cholangitis patients compared to healthy controls. Knockout of NK-1R decreased BDL-induced liver fibrosis, and treatment with L-733,060 resulted in decreased liver fibrosis in Mdr2–/– mice, which was shown by decreased sirius red staining, fibrosis gene and protein expression, and reduced transforming growth factor-β1 levels in serum and cholangiocyte supernatants. Furthermore, we observed that reduced liver fibrosis in NK-1R–/– mice with BDL surgery or Mdr2–/– mice treated with L-733,060 was associated with enhanced cellular senescence of hepatic stellate cells and decreased senescence of cholangiocytes. In vitro, L-733,060 inhibited SP-induced expression of fibrotic genes in hepatic stellate cells and cholangiocytes; treatment with L-733,060 partially reversed the SP-induced decrease of senescence gene expression in cultured hepatic stellate cells and the SP-induced increase of senescence-related gene expression in cultured cholangiocytes. Conclusion: Collectively, our results demonstrate the regulatory effects of the SP/NK-1R axis on liver fibrosis through changes in cellular senescence during cholestatic liver injury. (Hepatology 2017;66:528–541).

AB - Substance P (SP) is involved in the proliferation of cholangiocytes in bile duct–ligated (BDL) mice and human cholangiocarcinoma growth by interacting with the neurokinin-1 receptor (NK-1R). To identify whether SP regulates liver fibrosis during cholestasis, wild-type or NK-1R knockout (NK-1R–/–) mice that received BDL or sham surgery and multidrug resistance protein 2 knockout (Mdr2–/–) mice treated with either an NK-1R antagonist (L-733,060) or saline were used. Additionally, wild-type mice were treated with SP or saline intraperitoneally. In vivo, there was increased expression of tachykinin precursor 1 (coding SP) and NK-1R in both BDL and Mdr2–/– mice compared to wild-type mice. Expression of tachykinin precursor 1 and NK-1R was significantly higher in liver samples from primary sclerosing cholangitis patients compared to healthy controls. Knockout of NK-1R decreased BDL-induced liver fibrosis, and treatment with L-733,060 resulted in decreased liver fibrosis in Mdr2–/– mice, which was shown by decreased sirius red staining, fibrosis gene and protein expression, and reduced transforming growth factor-β1 levels in serum and cholangiocyte supernatants. Furthermore, we observed that reduced liver fibrosis in NK-1R–/– mice with BDL surgery or Mdr2–/– mice treated with L-733,060 was associated with enhanced cellular senescence of hepatic stellate cells and decreased senescence of cholangiocytes. In vitro, L-733,060 inhibited SP-induced expression of fibrotic genes in hepatic stellate cells and cholangiocytes; treatment with L-733,060 partially reversed the SP-induced decrease of senescence gene expression in cultured hepatic stellate cells and the SP-induced increase of senescence-related gene expression in cultured cholangiocytes. Conclusion: Collectively, our results demonstrate the regulatory effects of the SP/NK-1R axis on liver fibrosis through changes in cellular senescence during cholestatic liver injury. (Hepatology 2017;66:528–541).

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