Amelioration of Large Bile Duct Damage by Histamine-2 Receptor Vivo-Morpholino Treatment

Histamine binds to one of the four G-protein–coupled receptors expressed by large cholangiocytes. Histamine specifically increases large cholangiocyte proliferation via H2 histamine receptor (H2HR), which is increased in patients with primary sclerosing cholangitis (PSC). Ranitidine decreases liver damage in Mdr2-/- (Abcb4 null) mice. We targeted hepatic H2HR in Mdr2-/- mice using Vivo-Morpholino. Wild-type and Mdr2-/- mice were treated with mismatch or H2HR Vivo-Morpholino by tail vein injection for one week. Liver damage, mast cell (MC) activation, biliary H2HR, and HA serum levels were studied. MC markers were determined by qPCR for chymase and c-kit in total liver. Biliary mass was detected by CK-19 along with F4/80 to evaluate inflammation (with semi-quantification). Biliary senescence was determined by immunofluorescence and SA-β-gal staining. Hepatic fibrosis was evaluated by staining for desmin, Sirius Red/Fast Green, and vimentin. Immunofluorescence for transforming growth factor-β1, vascular endothelial growth factor-A/C, cyclic AMP/extracellular signal-regulated kinase expression was performed. Transforming growth factor-β1 and vascular endothelial growth factor -A secretion was measured in serum and/or cholangiocyte supernatant. Treatment with H2HR Vivo-Morpholino in Mdr2-/- - mice decreased i) hepatic damage; ii) H2HR protein expression and MC presence/activation; iii) large intrahepatic bile duct mass/ inflammation and senescence; iv) fibrosis, angiogenesis, and cyclic AMP/phospho extracellular signal-regulated kinase expression. Inhibition of H2HR signaling ameliorates large ductal PSC-induced damage. The H2HR axis may be targeted in treating PSC.