title: Inhibition of mast cell-secreted histamine decreases biliary proliferation and fibrosis in primary sclerosing cholangitis Mdr2(-/-) mice.
abstract: Hepatic fibrosis is marked by activation of hepatic stellate cells (HSCs). Cholestatic injury precedes liver fibrosis, and cholangiocytes interact with HSCs promoting fibrosis. Mast cells (MCs) infiltrate following liver injury and release histamine, increasing biliary proliferation. We evaluated if inhibition of MC-derived histamine decreases biliary proliferation and fibrosis. Wild-type and multidrug resistance 2 knockout mice (9-11 weeks) were treated with cromolyn sodium for 1 week to block MC-derived histamine. Biliary mass and proliferation were evaluated by immunohistochemistry for cytokeratin 19 and Ki-67. Bile flow, bicarbonate excretion, and total bile acids were measured in all mice. Fibrosis was evaluated by sirius red/fast green staining and by quantitative polymerase chain reaction for alpha-smooth muscle actin, fibronectin, collagen type 1a, and transforming growth factor-beta 1. HSC activation was evaluated by quantitative polymerase chain reaction in total liver and immunofluorescent staining in tissues for synaptophysin 9. Histamine serum secretion was measured by enzymatic immunoassay. Mouse liver and human liver samples from control or primary sclerosing cholangitis patients were evaluated for MC markers by quantitative polymerase chain reaction and immunohistochemistry. In vitro, cultured MCs were transfected with histidine decarboxylase short hairpin RNA to decrease histamine secretion and subsequently cocultured with cholangiocytes or HSCs prior to measuring fibrosis markers, proliferation, and transforming growth factor-beta 1 secretion. Treatment with cromolyn sodium decreased biliary proliferation, fibrosis, histamine secretion, and bile flow in multidrug resistance 2 knockout mice. Primary sclerosing cholangitis mice and patients have increased MCs. Knockdown of MC histidine decarboxylase decreased cholangiocyte and HSC proliferation/activation.
  
  
  
  MCs are recruited to proliferating cholangiocytes and promote fibrosis. Inhibition of MC-derived histamine decreases fibrosis, and regulation of MC mediators may be therapeutic for primary sclerosing cholangitis. (Hepatology 2016;64:1202-1216).
authors.affiliation: Scott & White Digestive Disease Research Center, Baylor Scott & White Health, Rozzano, Milan, Italy.
authors.forename: Hannah
authors.initials: H
authors.lastname: Jones
authors.affiliation: Scott & White Digestive Disease Research Center, Baylor Scott & White Health, Rozzano, Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Hargrove
authors.affiliation: Research, Central Texas Veterans Health Care System, Rozzano, Milan, Italy.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Kennedy
authors.affiliation: Research, Central Texas Veterans Health Care System, Rozzano, Milan, Italy.|Scott & White Digestive Disease Research Center, Baylor Scott & White Health, Rozzano, Milan, Italy.|Medicine, Texas A&M Health Science Center, Rozzano, Milan, Italy.
authors.forename: Fanyin
authors.initials: F
authors.lastname: Meng
authors.affiliation: Research, Central Texas Veterans Health Care System, Rozzano, Milan, Italy.
authors.forename: Allyson
authors.initials: A
authors.lastname: Graf-Eaton
authors.affiliation: Research, Central Texas Veterans Health Care System, Rozzano, Milan, Italy.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Owens
authors.affiliation: Research, Central Texas Veterans Health Care System, Rozzano, Milan, Italy.|Medicine, Texas A&M Health Science Center, Rozzano, Milan, Italy.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Alpini
authors.affiliation: Medicine, Texas A&M Health Science Center, Rozzano, Milan, Italy.
authors.forename: Christopher
authors.initials: C
authors.lastname: Johnson
authors.affiliation: Temple, Texas, USA and Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Bernuzzi
authors.affiliation: Research, Central Texas Veterans Health Care System, Rozzano, Milan, Italy.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Demieville
authors.affiliation: Research, Central Texas Veterans Health Care System, Rozzano, Milan, Italy.|Medicine, Texas A&M Health Science Center, Rozzano, Milan, Italy.
authors.forename: Sharon
authors.initials: S
authors.lastname: DeMorrow
authors.affiliation: Temple, Texas, USA and Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Invernizzi
authors.affiliation: Research, Central Texas Veterans Health Care System, Rozzano, Milan, Italy.|Scott & White Digestive Disease Research Center, Baylor Scott & White Health, Rozzano, Milan, Italy.|Medicine, Texas A&M Health Science Center, Rozzano, Milan, Italy.
authors.forename: Heather
authors.initials: H
authors.lastname: Francis
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000502:physiology; D000818:Animals; D001659:Biliary Tract / Q000473:pathology; D049109:Cell Proliferation; D015209:Cholangitis, Sclerosing / Q000473:pathology*; D006636:Histamine Release; D008297:Male; D008407:Mast Cells / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000097202:ATP-Binding Cassette Sub-Family B Member 4