{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:31:43Z","timestamp":1789605103437,"version":"build-2803163510"},"reference-count":46,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2017,4,28]],"date-time":"2017-04-28T00:00:00Z","timestamp":1493337600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"},{"start":{"date-parts":[[2017,4,28]],"date-time":"2017-04-28T00:00:00Z","timestamp":1493337600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2017,6]]},"abstract":"<jats:p>Activated mast cells (MCs) release histamine (HA) and MCs infiltrate the liver following bile duct ligation (BDL), increasing intrahepatic bile duct mass (IBDM) and fibrosis. We evaluated the effects of BDL in MC\u2010deficient (<jats:italic toggle=\"yes\">KitW\u2010sh\n                           <\/jats:italic>) mice. Wild\u2010type (WT) and <jats:italic toggle=\"yes\">KitW\u2010sh\n                           <\/jats:italic> mice were subjected to sham or BDL for up to 7 days and <jats:italic toggle=\"yes\">KitW\u2010sh\n                           <\/jats:italic> mice were injected with cultured mast cells or 1\u00d7 phosphate\u2010buffered saline (PBS) before collecting serum, liver, and cholangiocytes. Liver damage was assessed by hematoxylin and eosin and alanine aminotransferase levels. IBDM was detected by cytokeratin\u201019 expression and proliferation by Ki\u201067 immunohistochemistry (IHC). Fibrosis was detected by IHC, hydroxyproline content, and by qPCR for fibrotic markers. Hepatic stellate cell (HSC) activation and transforming growth factor\u2010beta 1 (TGF\u2010\u03b21) expression\/secretion were evaluated. Histidine decarboxylase (HDC) and histamine receptor (HR) expression were detected by qPCR and HA secretion by enzymatic immunoassay. To evaluate vascular cells, von Willebrand factor (vWF) and vascular endothelial growth factor (VEGF)\u2010C expression were measured. <jats:italic toggle=\"yes\">In vitro<\/jats:italic>, cultured HSCs were stimulated with cholangiocyte supernatants and alpha\u2010smooth muscle actin levels were measured. BDL\u2010induced liver damage was reduced in BDL <jats:italic toggle=\"yes\">KitW\u2010sh\n                           <\/jats:italic> mice, whereas injection of MCs did not mimic BDL\u2010induced damage. In BDL <jats:italic toggle=\"yes\">KitW\u2010sh\n                           <\/jats:italic> mice, IBDM, proliferation, HSC activation\/fibrosis, and TGF\u2010\u03b21 expression\/secretion were decreased. The HDC\/HA\/HR axis was ablated in sham and BDL <jats:italic toggle=\"yes\">KitW\u2010sh\n                           <\/jats:italic> mice. vWF and VEGF\u2010C expression decreased in BDL <jats:italic toggle=\"yes\">KitW\u2010sh\n                           <\/jats:italic> mice. In <jats:italic toggle=\"yes\">KitW\u2010sh\n                           <\/jats:italic> mice injected with MCs, IBDM, proliferation, fibrosis, and vascular cell activation increased. Stimulation with cholangiocyte supernatants from BDL WT or <jats:italic toggle=\"yes\">KitW\u2010sh\n                           <\/jats:italic> mice injected with MCs increased HSC activation, which decreased with supernatants from BDL <jats:italic toggle=\"yes\">KitW\u2010sh\n                           <\/jats:italic> mice. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: MCs promote hyperplasia, fibrosis, and vascular cell activation. Knockout of MCs decreases BDL\u2010induced damage. Modulation of MCs may be important in developing therapeutics for cholangiopathies. (H<jats:sc>epatology<\/jats:sc> 2017;65:1991\u20102004).<\/jats:p>","DOI":"10.1002\/hep.29079","type":"journal-article","created":{"date-parts":[[2017,1,25]],"date-time":"2017-01-25T03:42:44Z","timestamp":1485315764000},"page":"1991-2004","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":62,"title":["Bile duct ligation\u2013induced biliary hyperplasia, hepatic injury, and fibrosis are reduced in mast cell\u2013deficient KitW\u2010sh mice"],"prefix":"10.1097","volume":"65","author":[{"given":"Laura","family":"Hargrove","sequence":"first","affiliation":[{"name":"Digestive Disease Research Center,Baylor Scott & White Health,Temple,TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsey","family":"Kennedy","sequence":"additional","affiliation":[{"name":"Research Service,Central Texas Veterans Health Care System,Temple,TX"},{"name":"Texas A&M Health Science Center\/College of Medicine,Temple,TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Demieville","sequence":"additional","affiliation":[{"name":"Research Service,Central Texas Veterans Health Care System,Temple,TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Jones","sequence":"additional","affiliation":[{"name":"Digestive Disease Research Center,Baylor Scott & White Health,Temple,TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanyin","family":"Meng","sequence":"additional","affiliation":[{"name":"Research Service,Central Texas Veterans Health Care System,Temple,TX"},{"name":"Digestive Disease Research Center,Baylor Scott & White Health,Temple,TX"},{"name":"Texas A&M Health Science Center\/College of Medicine,Temple,TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon","family":"DeMorrow","sequence":"additional","affiliation":[{"name":"Research Service,Central Texas Veterans Health Care System,Temple,TX"},{"name":"Texas A&M Health Science Center\/College of Medicine,Temple,TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walker","family":"Karstens","sequence":"additional","affiliation":[{"name":"Digestive Disease Research Center,Baylor Scott & White Health,Temple,TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taronish","family":"Madeka","sequence":"additional","affiliation":[{"name":"Digestive Disease Research Center,Baylor Scott & White Health,Temple,TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Greene","sequence":"additional","affiliation":[{"name":"Digestive Disease Research Center,Baylor Scott & White Health,Temple,TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Francis","sequence":"additional","affiliation":[{"name":"Research Service,Central Texas Veterans Health Care System,Temple,TX"},{"name":"Digestive Disease Research Center,Baylor Scott & White Health,Temple,TX"},{"name":"Texas A&M Health Science Center\/College of Medicine,Temple,TX"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2017,4,28]]},"reference":[{"key":"hep29079-bib-0002-20241017","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1053\/j.gastro.2013.06.052","article-title":"Pathogenesis of primary sclerosing cholangitis and advances in diagnosis and management","volume":"145","year":"2013","journal-title":"Gastroenterology"},{"key":"hep29079-bib-0003-20241017","doi-asserted-by":"crossref","first-page":"1789","DOI":"10.1097\/MIB.0b013e318281f49a","article-title":"Genetic and epigenetic abnormalities in primary sclerosing cholangitis\u2010associated cholangiocarcinoma","volume":"19","year":"2013","journal-title":"Inflamm Bowel Dis"},{"key":"hep29079-bib-0004-20241017","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.1053\/j.gastro.2014.02.030","article-title":"Secretin stimulates biliary cell proliferation by regulating expression of microRNA 125b and microRNA let7a in mice","volume":"146","year":"2014","journal-title":"Gastroenterology"},{"key":"hep29079-bib-0005-20241017","doi-asserted-by":"crossref","first-page":"G307","DOI":"10.1152\/ajpgi.00507.2005","article-title":"Administration of r\u2010VEGF\u2010A prevents hepatic artery ligation\u2010induced bile duct damage in bile duct ligated rats","volume":"291","year":"2006","journal-title":"Am J Physiol Gastrointet Liver Physiol"},{"key":"hep29079-bib-0006-20241017","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1053\/j.gastro.2005.12.034","article-title":"Vascular endothelial growth factor stimulates rat cholangiocyte proliferation via an autocrine mechanism","volume":"130","year":"2006","journal-title":"Gastroenterology"},{"key":"hep29079-bib-0007-20241017","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1038\/labinvest.3700533","article-title":"H3 histamine receptor agonist inhibits biliary growth of BDL rats by downregulation of the cAMP\u2010dependent PKA\/ERK1\/2\/ELK\u20101 pathway","volume":"87","year":"2007","journal-title":"Lab Invest"},{"key":"hep29079-bib-0008-20241017","doi-asserted-by":"crossref","first-page":"C499","DOI":"10.1152\/ajpcell.00369.2007","article-title":"Small mouse cholangiocytes proliferate in response to H1 histamine receptor stimulation by activation of the IP3\/CaMK I\/CREB pathway","volume":"295","year":"2008","journal-title":"Am J Physiol Cell Physiol"},{"key":"hep29079-bib-0009-20241017","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1038\/labinvest.2011.158","article-title":"Histamine stimulates the proliferation of small and large cholangiocytes by activation of both IP(3)\/Ca(2+) and cAMP\u2010dependent signaling mechanisms","volume":"92","year":"2012","journal-title":"Lab Invest"},{"key":"hep29079-bib-0010-20241017","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1136\/gutjnl-2014-306842","article-title":"Pathobiology of liver fibrosis: a translational success story","volume":"64","year":"2015","journal-title":"Gut"},{"key":"hep29079-bib-0011-20241017","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.bpg.2011.02.001","article-title":"Fibrosis in autoimmune and cholestatic liver disease","volume":"25","year":"2011","journal-title":"Best Pract Res Clin Gastroenterol"},{"key":"hep29079-bib-0012-20241017","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1002\/hep.23019","article-title":"Repair\u2010related activation of hedgehog signaling promotes cholangiocyte chemokine production","volume":"50","year":"2009","journal-title":"Hepatology"},{"key":"hep29079-bib-0013-20241017","doi-asserted-by":"crossref","first-page":"G303","DOI":"10.1152\/ajpgi.00368.2010","article-title":"Paracrine modulation of cholangiocyte serotonin synthesis orchestrates biliary remodeling in adults","volume":"300","year":"2011","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"hep29079-bib-0014-20241017","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.cbi.2015.08.013","article-title":"Chrysin attenuates liver fibrosis and hepatic stellate cell activation through TGF\u2010beta\/Smad signaling pathway","volume":"240","year":"2015","journal-title":"Chem Biol Interact"},{"key":"hep29079-bib-0015-20241017","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.hepres.2005.01.007","article-title":"A role of mast cells for hepatic fibrosis in primary sclerosing cholangitis","volume":"31","year":"2005","journal-title":"Hepatol Res"},{"key":"hep29079-bib-0016-20241017","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/j.iac.2006.05.007","article-title":"Mast cells: not only in allergy","volume":"26","year":"2006","journal-title":"Immunol Allergy Clin North Am"},{"key":"hep29079-bib-0017-20241017","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.ajpath.2015.09.016","article-title":"Inhibition of mast cell\u2010derived histamine decreases human cholangiocarcinoma growth and differentiation via c\u2010Kit\/stem cell factor\u2010dependent signaling","volume":"186","year":"2016","journal-title":"Am J Pathol"},{"key":"hep29079-bib-0018-20241017","doi-asserted-by":"crossref","first-page":"1406","DOI":"10.1038\/labinvest.2014.129","article-title":"Inhibition of mast cell\u2010derived histamine secretion by cromolyn sodium treatment decreases biliary hyperplasia in cholestatic rodents","volume":"94","year":"2014","journal-title":"Lab Invest"},{"key":"hep29079-bib-0019-20241017","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1002\/hep.28704","article-title":"Inhibition of mast cell\u2010secreted histamine decreases biliary proliferation and fibrosis in primary sclerosing cholangitis Mdr2\u2013\/\u2013 mice","volume":"64","year":"2016","journal-title":"Hepatology"},{"key":"hep29079-bib-0020-20241017","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/S0168-8278(98)80185-2","article-title":"Mast cell, myofibroblast and nerve terminal complexes in carbon tetrachloride\u2010induced cirrhotic rat livers","volume":"29","year":"1998","journal-title":"J Hepatol"},{"key":"hep29079-bib-0021-20241017","first-page":"119","article-title":"Mast cell chemotaxis\u2014chemoattractants and signaling pathways","volume":"3","year":"2012","journal-title":"Front Immunol"},{"key":"hep29079-bib-0022-20241017","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1002\/eji.200838899","article-title":"Our perception of the mast cell from Paul Ehrlich to now","volume":"39","year":"2009","journal-title":"Eur J Immunol"},{"key":"hep29079-bib-0023-20241017","first-page":"27","article-title":"The biology of the mast cell","volume":"25","year":"2004","journal-title":"Allergy Asthma Proc"},{"key":"hep29079-bib-0024-20241017","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1093\/genetics\/97.2.337","article-title":"Analysis of pleiotropism at the dominant white\u2010spotting (W) locus of the house mouse: a description of ten new W alleles","volume":"97","year":"1981","journal-title":"Genetics"},{"key":"hep29079-bib-0025-20241017","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1016\/S0002-9440(10)62055-X","article-title":"Mast cell\u2010deficient W\u2010sash c\u2010kit mutant Kit W\u2010sh\/W\u2010sh mice as a model for investigating mast cell biology in vivo","volume":"167","year":"2005","journal-title":"Am J Pathol"},{"key":"hep29079-bib-0026-20241017","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1182\/blood.V52.2.447.447","article-title":"Decrease of mast cells in W\/Wv mice and their increase by bone marrow transplantation","volume":"52","year":"1978","journal-title":"Blood"},{"key":"hep29079-bib-0027-20241017","doi-asserted-by":"crossref","first-page":"1936","DOI":"10.1182\/blood.V78.8.1936.1936","article-title":"Anemia and mast cell depletion in mutant rats that are homozygous at \u201cwhite spotting (Ws)\u201d locus","volume":"78","year":"1991","journal-title":"Blood"},{"key":"hep29079-bib-0028-20241017","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1136\/gutjnl-2011-300007","article-title":"Inhibition of histidine decarboxylase ablates the autocrine tumorigenic effects of histamine in human cholangiocarcinoma","volume":"61","year":"2012","journal-title":"Gut"},{"key":"hep29079-bib-0029-20241017","doi-asserted-by":"crossref","first-page":"G813","DOI":"10.1152\/ajpgi.00188.2014","article-title":"Knockout of histidine decarboxylase decreases bile duct ligation\u2010induced biliary hyperplasia via downregulation of the histidine decarboxylase\/VEGF axis through PKA\u2010ERK1\/2 signaling","volume":"307","year":"2014","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"hep29079-bib-0030-20241017","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1016\/j.ajpath.2013.11.008","article-title":"Regulation of the histamine\/VEGF axis by miR\u2010125b during cholestatic liver injury in mice","volume":"184","year":"2014","journal-title":"Am J Pathol"},{"key":"hep29079-bib-0031-20241017","doi-asserted-by":"crossref","first-page":"6203","DOI":"10.1038\/onc.2010.348","article-title":"Mast cells have a protumorigenic role in human thyroid cancer","volume":"29","year":"2010","journal-title":"Oncogene"},{"key":"hep29079-bib-0032-20241017","doi-asserted-by":"crossref","first-page":"1831","DOI":"10.1016\/S0002-9440(10)65501-0","article-title":"Synaptophysin: a novel marker for human and rat hepatic stellate cells","volume":"155","year":"1999","journal-title":"Am J Pathol"},{"key":"hep29079-bib-0033-20241017","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1016\/S0002-9440(10)63487-6","article-title":"Capillarization of hepatic sinusoid by liver endothelial cell\u2010reactive autoantibodies in patients with cirrhosis and chronic hepatitis","volume":"163","year":"2003","journal-title":"Am J Pathol"},{"key":"hep29079-bib-0034-20241017","doi-asserted-by":"crossref","first-page":"G1087","DOI":"10.1152\/ajpgi.00070.2013","article-title":"Pathogenic role of mast cells in experimental eosinophilic esophagitis","volume":"304","year":"2013","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"hep29079-bib-0035-20241017","doi-asserted-by":"crossref","first-page":"H2612","DOI":"10.1152\/ajpheart.00879.2011","article-title":"Mast cell deficiency attenuates progression of atherosclerosis and hepatic steatosis in apolipoprotein E\u2010null mice","volume":"302","year":"2012","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"hep29079-bib-0036-20241017","doi-asserted-by":"crossref","first-page":"2228","DOI":"10.1111\/j.1523-1755.2004.00629.x","article-title":"Role of mast cells in the development of renal fibrosis: use of mast cell\u2010deficient rats","volume":"65","year":"2004","journal-title":"Kidney Int"},{"key":"hep29079-bib-0037-20241017","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1084\/jem.20002036","article-title":"Evidence for a role of mast cells in the evolution to congestive heart failure","volume":"195","year":"2002","journal-title":"J Exp Med"},{"key":"hep29079-bib-0038-20241017","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1007\/s00018-013-1349-6","article-title":"The pathogenesis of cardiac fibrosis","volume":"71","year":"2014","journal-title":"Cell Mol Life Sci"},{"key":"hep29079-bib-0039-20241017","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1016\/S0168-8278(99)80140-8","article-title":"Evaluation of role of mast cells in the development of liver fibrosis using mast cell\u2010deficient rats and mice","volume":"30","year":"1999","journal-title":"J Hepatol"},{"key":"hep29079-bib-0040-20241017","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1089\/dna.2013.2005","article-title":"Mast cells: a pivotal role in pulmonary fibrosis","volume":"32","year":"2013","journal-title":"DNA Cell Biol"},{"key":"hep29079-bib-0041-20241017","doi-asserted-by":"crossref","first-page":"2751","DOI":"10.1111\/jcmm.12703","article-title":"The cardiac repair benefits of inflammation do not persist: evidence from mast cell implantation","volume":"19","year":"2015","journal-title":"J Cell Mol Med"},{"key":"hep29079-bib-0042-20241017","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.bbrc.2010.09.047","article-title":"VEGF secretion during hypoxia depends on free radicals\u2010induced Fyn kinase activity in mast cells","volume":"401","year":"2010","journal-title":"Biochem Biophys Res Commun"},{"key":"hep29079-bib-0043-20241017","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1186\/1756-8722-6-56","article-title":"Immunoglobulin E induces VEGF production in mast cells and potentiates their pro\u2010tumorigenic actions through a Fyn kinase\u2010dependent mechanism","volume":"6","year":"2013","journal-title":"J Hematol Oncol"},{"key":"hep29079-bib-0044-20241017","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.ydbio.2009.10.021","article-title":"Mast cells contribute to the stromal microenvironment in mammary gland branching morphogenesis","volume":"337","year":"2010","journal-title":"Dev Biol"},{"key":"hep29079-bib-0045-20241017","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1053\/j.gastro.2004.10.002","article-title":"Autocrine\/paracrine regulation of the growth of the biliary tree by the neuroendocrine hormone serotonin","volume":"128","year":"2005","journal-title":"Gastroenterology"},{"key":"hep29079-bib-0046-20241017","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1084\/jem.20011782","article-title":"Defective angiogenesis in the inflammatory granulation tissue in histidine decarboxylase\u2010deficient mice but not in mast cell\u2010deficient mice","volume":"195","year":"2002","journal-title":"J Exp Med"},{"key":"hep29079-bib-0047-20241017","doi-asserted-by":"crossref","first-page":"e0123575","DOI":"10.1371\/journal.pone.0123575","article-title":"Down\u2010regulation of microRNA\u2010223 promotes degranulation via the PI3K\/Akt pathway by targeting IGF\u20101R in mast cells","volume":"10","year":"2015","journal-title":"PLoS One"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.29079","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-201706000-00025","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,17]],"date-time":"2024-10-17T23:53:12Z","timestamp":1729209192000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-201706000-00025"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,4,28]]},"references-count":46,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2017]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.29079","relation":{},"ISSN":["0270-9139","1527-3350"],"issn-type":[{"value":"0270-9139","type":"print"},{"value":"1527-3350","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,4,28]]},"assertion":[{"value":"2016-07-13","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-01-19","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}