title: Substance P increases liver fibrosis by differential changes in senescence of cholangiocytes and hepatic stellate cells.
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.
  
  
  
  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).
authors.affiliation: Research, Central Texas Veterans Health Care System.|Baylor Scott & White Digestive Disease Research Center, Scott & White, Temple, TX.|Department of Pathophysiology, Key Lab for Shock and Microcirculation Research of Guangdong Province, Southern Medical University, Guangzhou, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wan
authors.affiliation: Research, Central Texas Veterans Health Care System.|Baylor Scott & White Digestive Disease Research Center, Scott & White, Temple, TX.|Operational Funds, Baylor Scott & White Health.|Department of Medicine, Division of Gastroenterology, Texas A&M University Health Science Center and Baylor Scott & White Health, Temple, TX.
authors.forename: Fanyin
authors.initials: F
authors.lastname: Meng
authors.affiliation: Department of Medicine, Division of Gastroenterology, Texas A&M University Health Science Center and Baylor Scott & White Health, Temple, TX.
authors.forename: Nan
authors.initials: N
authors.lastname: Wu
authors.affiliation: Department of Medicine, Division of Gastroenterology, Texas A&M University Health Science Center and Baylor Scott & White Health, Temple, TX.
authors.forename: Tianhao
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Department of Medicine, Division of Gastroenterology, Texas A&M University Health Science Center and Baylor Scott & White Health, Temple, TX.
authors.forename: Julie
authors.initials: J
authors.lastname: Venter
authors.affiliation: Research, Central Texas Veterans Health Care System.|Baylor Scott & White Digestive Disease Research Center, Scott & White, Temple, TX.|Department of Medicine, Division of Gastroenterology, Texas A&M University Health Science Center and Baylor Scott & White Health, Temple, TX.
authors.forename: Heather
authors.initials: H
authors.lastname: Francis
authors.affiliation: Department of Medicine, Division of Gastroenterology, Texas A&M University Health Science Center and Baylor Scott & White Health, Temple, TX.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Kennedy
authors.affiliation: Baylor Scott & White Digestive Disease Research Center, Scott & White, Temple, TX.
authors.forename: Trenton
authors.initials: T
authors.lastname: Glaser
authors.affiliation: Humanitas Clinical and Research Center, Rozzano, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Bernuzzi
authors.affiliation: Humanitas Clinical and Research Center, Rozzano, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Invernizzi
authors.affiliation: Research, Central Texas Veterans Health Care System.|Baylor Scott & White Digestive Disease Research Center, Scott & White, Temple, TX.|Department of Medicine, Division of Gastroenterology, Texas A&M University Health Science Center and Baylor Scott & White Health, Temple, TX.
authors.forename: Shannon
authors.initials: S
authors.lastname: Glaser
authors.affiliation: Department of Pathophysiology, Key Lab for Shock and Microcirculation Research of Guangdong Province, Southern Medical University, Guangzhou, China.
authors.forename: Qiaobing
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Research, Central Texas Veterans Health Care System.|Baylor Scott & White Digestive Disease Research Center, Scott & White, Temple, TX.|Department of Medicine, Division of Gastroenterology, Texas A&M University Health Science Center and Baylor Scott & White Health, Temple, TX.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Alpini
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001652:Bile Ducts / Q000166:cytology*; D015415:Biomarkers / Q000378:metabolism; D001707:Biopsy, Needle; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008103:Liver Cirrhosis / Q000473:pathology*; D008111:Liver Function Tests; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D012680:Sensitivity and Specificity; D013373:Substance P / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D012333:RNA, Messenger; D013373:Substance P