title: Inhibition of mast cell-derived histamine secretion by cromolyn sodium treatment decreases biliary hyperplasia in cholestatic rodents.
abstract: Cholangiopathies are characterized by dysregulation of the balance between biliary growth and loss. We have shown that histamine (HA) stimulates biliary growth via autocrine mechanisms. To evaluate the paracrine effects of mast cell (MC) stabilization on biliary proliferation, sham or BDL rats were treated by IP-implanted osmotic pumps filled with saline or cromolyn sodium (24 mg/kg BW/day (inhibits MC histamine release)) for 1 week. Serum, liver blocks and cholangiocytes were collected. Histidine decarboxylase (HDC) expression was measured using real-time PCR in cholangiocytes. Intrahepatic bile duct mass (IBDM) was evaluated by IHC for CK-19. MC number was determined using toluidine blue staining and correlated to IBDM. Proliferation was evaluated by PCNA expression in liver sections and purified cholangiocytes. We assessed apoptosis using real-time PCR and IHC for BAX. Expression of MC stem factor receptor, c-kit, and the proteases chymase and tryptase were measured by real-time PCR. HA levels were measured in serum by EIA. In vitro, MCs and cholangiocytes were treated with 0.1% BSA (basal) or cromolyn (25 μM) for up to 48 h prior to assessing HDC expression, HA levels and chymase and tryptase expression. Supernatants from MCs treated with or without cromolyn were added to cholangiocytes before measuring (i) proliferation by MTT assays, (ii) HDC gene expression by real-time PCR and (iii) HA release by EIA. In vivo, cromolyn treatment decreased BDL-induced: (i) IBDM, MC number, and biliary proliferation; (ii) HDC and MC marker expression; and (iii) HA levels. Cromolyn treatment increased cholangiocyte apoptosis. In vitro, cromolyn decreased HA release and chymase and tryptase expression in MCs but not in cholangiocytes. Cromolyn-treated MC supernatants decreased biliary proliferation and HA release. These studies provide evidence that MC histamine is key to biliary proliferation and may be a therapeutic target for the treatment of cholangiopathies.
authors.affiliation: Digestive Disease Research Center, Central Texas Veterans Health Care System, Temple, TX, USA.
authors.forename: Lindsey L
authors.initials: LL
authors.lastname: Kennedy
authors.affiliation: Scott and White Digestive Disease Research Center, Scott and White, Temple, TX, USA.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Hargrove
authors.affiliation: Digestive Disease Research Center, Central Texas Veterans Health Care System, Temple, TX, USA.
authors.forename: Allyson B
authors.initials: AB
authors.lastname: Graf
authors.affiliation: Department of Medicine, Texas A&M Health Science Center, Temple, TX, USA.
authors.forename: Taylor C
authors.initials: TC
authors.lastname: Francis
authors.affiliation: Scott and White Digestive Disease Research Center, Scott and White, Temple, TX, USA.
authors.forename: Kyle M
authors.initials: KM
authors.lastname: Hodges
authors.affiliation: Digestive Disease Research Center, Central Texas Veterans Health Care System, Temple, TX, USA.
authors.forename: Quy P
authors.initials: QP
authors.lastname: Nguyen
authors.affiliation: CREST, Japan Science and Technology Corporation, Tokyo, Japan.
authors.forename: Yoshi
authors.initials: Y
authors.lastname: Ueno
authors.affiliation: Scott and White Digestive Disease Research Center, Scott and White, Temple, TX, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Greene
authors.affiliation: 1] Digestive Disease Research Center, Central Texas Veterans Health Care System, Temple, TX, USA [2] Scott and White Digestive Disease Research Center, Scott and White, Temple, TX, USA [3] Department of Medicine, Texas A&M Health Science Center, Temple, TX, USA.
authors.forename: Fanyin
authors.initials: F
authors.lastname: Meng
authors.affiliation: Department of Medicine, Texas A&M Health Science Center, Temple, TX, USA.
authors.forename: Victoria D
authors.initials: VD
authors.lastname: Huynh
authors.affiliation: 1] Digestive Disease Research Center, Central Texas Veterans Health Care System, Temple, TX, USA [2] Scott and White Digestive Disease Research Center, Scott and White, Temple, TX, USA [3] Department of Medicine, Texas A&M Health Science Center, Temple, TX, USA.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Francis
mesh_terms: D000818:Animals; D001653:Bile Ducts, Intrahepatic / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D002779:Cholestasis / Q000188:drug therapy*; D004205:Cromolyn Sodium / Q000494:pharmacology*; D004195:Disease Models, Animal; D006636:Histamine Release / Q000187:drug effects*; D008297:Male; D008407:Mast Cells / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D004205:Cromolyn Sodium