title: Inhibition of acidic sphingomyelinase reduces established hepatic fibrosis in mice.
abstract: OBJECTIVE
  Liver fibrosis occurs as a result of several chronic liver diseases and leads to portal hypertension, cirrhosis and liver failure, often requiring liver transplantation. Activated hepatic stellate cells (HSC) are known to contribute to liver fibrosis, but currently there are no effective therapies for the treatment of established liver fibrosis. Activation of the acidic sphingomyelinase (ASM) has been shown to be involved in HSC activation. In the present study we investigated whether treatment with the ASM inhibitor, amitriptyline (TCA), could prevent and/or reverse fibrosis induced in mice by carbon tetrachloride (CCl4 ).
  
  
  METHODS
  Mice were treated with CCl4 for 8 weeks to induce fibrosis. Concurrently, mice received drinking water with or without 180 mg/L TCA.
  
  
  RESULTS
  Mice receiving TCA in the water had decreased hepatic collagen deposition and reduced liver mRNA expression of the fibrogenic mediators, transforming growth factor (TGF)-β1, tissue inhibitor of matrix metalloproteinase-1, collagen and tumor necrosis factor-α. TCA treatment also reduced HSC activation determined by α-smooth muscle actin staining. In a separate set of experiments, mice were treated with CCl4 for 5 weeks prior to treatment with TCA, to test whether TCA had any effect on established fibrosis. Remarkably, in mice with established fibrosis, treatment with TCA significantly reduced collagen deposition, HSC activation, and prevented portal hypertension and improved hepatic architecture. Treatment of isolated HSC in vitro with TCA completely inhibited TGF-β1-induced collagen expression and platelet-derived growth factor-β-β-induced proliferation.
  
  
  CONCLUSIONS
  The data suggest that ASM is a critical signaling component in HSC for the development of liver fibrosis and represents an important therapeutic target.
authors.affiliation: Department of Surgery, Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Ralph C
authors.initials: RC
authors.lastname: Quillin
authors.forename: Gregory C
authors.initials: GC
authors.lastname: Wilson
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nojima
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Freeman
authors.forename: Jiang
authors.initials: J
authors.lastname: Wang
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Schuster
authors.forename: John A
authors.initials: JA
authors.lastname: Blanchard
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Edwards
authors.forename: Chandrashekhar R
authors.initials: CR
authors.lastname: Gandhi
authors.forename: Erich
authors.initials: E
authors.lastname: Gulbins
authors.forename: Alex B
authors.initials: AB
authors.lastname: Lentsch
keywords: liver fibrosis; non-alcoholic steatohepatitis; stellate cells