Wan Y, Meng F, Wu N et al.
Research, Central Texas Veterans Health Care System.
Hepatology (Baltimore, Md.). Mar 2017.
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 (WT) or NK-1R knockout (NK-1R(-/-) ) mice that received BDL or sham surgery and Mdr2(-/-) mice treated with either an NK-1R antagonist (L-733,060) or saline were used. Additionally, WT mice were treated with SP or saline intraperitoneally. In vivo, there was increased expression of TAC1 (coding SP) and NK-1R in both BDL and Mdr2(-/-) mice compared to WT mice. The expression of TAC1 and NK-1R was significantly higher in liver samples from PSC 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 cholangiocytes 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 (HSCs) and decreased senescence of cholangiocytes. In vitro, L-733,060 inhibited SP-induced expression of fibrotic genes in HSCs and cholangiocytes. Treatment with L-733,060 partially reversed SP-induced decrease of senescence genes expression in cultured HSCs and SP-induced increase of senescence-related genes expression in cultured cholangiocytes. Collectively, our results demonstrated the regulatory effects of the SP/NK-1R axis on liver fibrosis through changes in cellular senescence during cholestatic liver injury. This article is protected by copyright. All rights reserved.