{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T01:56:05Z","timestamp":1768874165333,"version":"3.49.0"},"reference-count":46,"publisher":"American Physiological Society","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Gastrointestinal and Liver Physiology"],"published-print":{"date-parts":[[2011,8]]},"abstract":"<jats:p>In bile duct-ligated (BDL) rats, cholangiocyte proliferation is regulated by neuroendocrine factors such as \u03b1-calcitonin gene-related peptide (\u03b1-CGRP). There is no evidence that the sensory neuropeptide substance P (SP) regulates cholangiocyte hyperplasia. Wild-type (WT,<jats:sup>+\/+<\/jats:sup>) and NK-1 receptor (NK-1R) knockout (NK-1R<jats:sup>\u2212\/\u2212<\/jats:sup>) mice underwent sham or BDL for 1 wk. Then we evaluated 1) NK-1R expression, transaminases, and bilirubin serum levels; 2) necrosis, hepatocyte apoptosis and steatosis, and the number of cholangiocytes positive by CK-19 and terminal deoxynucleotidyl transferase biotin-dUTP nick-end labeling in liver sections; 3) mRNA expression for collagen 1\u03b1 and \u03b1-smooth muscle (\u03b1-SMA) actin in total liver samples; and 4) PCNA expression and PKA phosphorylation in cholangiocytes. In cholangiocyte lines, we determined the effects of SP on cAMP and d-myo-inositol 1,4,5-trisphosphate levels, proliferation, and PKA phosphorylation. Cholangiocytes express NK-1R with expression being upregulated following BDL. In normal NK-1R<jats:sup>\u2212\/\u2212<\/jats:sup>mice, there was higher hepatocyte apoptosis and scattered hepatocyte steatosis compared with controls. In NK-1R<jats:sup>\u2212<\/jats:sup>\/<jats:sup>\u2212<\/jats:sup>BDL mice, there was a decrease in serum transaminases and bilirubin levels and the number of CK-19-positive cholangiocytes and enhanced biliary apoptosis compared with controls. In total liver samples, the expression of collagen 1\u03b1 and \u03b1-SMA increased in BDL compared with normal mice and decreased in BDL NK-1R<jats:sup>\u2212\/\u2212<\/jats:sup>compared with BDL mice. In cholangiocytes from BDL NK-1R<jats:sup>\u2212<\/jats:sup>\/<jats:sup>\u2212<\/jats:sup>mice there was decreased PCNA expression and PKA phosphorylation. In vitro, SP increased cAMP levels, proliferation, and PKA phosphorylation of cholangiocytes. Targeting of NK-1R may be important in the inhibition of biliary hyperplasia in cholangiopathies.<\/jats:p>","DOI":"10.1152\/ajpgi.00418.2010","type":"journal-article","created":{"date-parts":[[2011,5,20]],"date-time":"2011-05-20T03:13:29Z","timestamp":1305861209000},"page":"G297-G305","source":"Crossref","is-referenced-by-count":34,"title":["Knockout of the neurokinin-1 receptor reduces cholangiocyte proliferation in bile duct-ligated mice"],"prefix":"10.1152","volume":"301","author":[{"given":"Shannon","family":"Glaser","sequence":"first","affiliation":[{"name":"Division of Research, Central Texas Veterans Health Care System,"},{"name":"Department of Medicine,"},{"name":"Scott &amp; White Digestive Disease Research Center, and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eugenio","family":"Gaudio","sequence":"additional","affiliation":[{"name":"Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, University of Rome \u201cLa 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