title: An orally available small imidazolium salt ameliorates inflammation and fibrosis in a murine model of cholestasis.
abstract: Hepatic fibrosis is the result of chronic liver injuries underlined by diverse etiologies. The massive accumulation of extracellular matrix (ECM) proteins during fibrogenesis leads to structural distortion and functional disruption of the liver. There is currently no effective standard treatment for liver fibrosis. We previously identified a class of imidazolium salts (IMSs) with anti-fibrotic properties in a cell-based screen. In this report, we investigated the anti-fibrotic efficacy and mechanisms of a small IMS, 1,3-diisopropylimidazolium tetrafluoroborate (DPIM), in a hepatic fibrosis model induced by bile duct ligation (BDL) in mice. The orally available DPIM was administered to BDL mice via drinking water at three concentrations (0.5, 0.75, and 1 g/l) for 4 weeks. We observed a significant reduction in inflammation and collagen deposition in the liver, which could be mediated by a reduction in the expression of monocyte chemoattractant protein-1 (MCP-1) and by an enhancement in the matrix metalloproteinase-mediated ECM remodeling. The current findings highlight the importance for simultaneously targeting multiple pathways to more effectively attenuate and resolve liver fibrosis and warrant further studies on this compound in additional models of hepatic fibrosis.
authors.affiliation: Institute of Bioengineering and Nanotechnology, The Nanos, Singapore.
authors.forename: Zhaobing
authors.initials: Z
authors.lastname: Ding
authors.forename: Yinling
authors.initials: Y
authors.lastname: Kng
authors.forename: Henry
authors.initials: H
authors.lastname: Yang
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Ke
authors.forename: Lang
authors.initials: L
authors.lastname: Zhuo
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002460:Cell Line; D002779:Cholestasis / Q000188:drug therapy*; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D005355:Fibrosis / Q000188:drug therapy*; D007093:Imidazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000188:drug therapy*; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D016133:Polymerase Chain Reaction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism
chemical_list: C558958:1,3-diisopropylimidazolium tetrafluoroborate; D007093:Imidazoles; D019715:Tissue Inhibitor of Metalloproteinase-1; D003094:Collagen; D020782:Matrix Metalloproteinases