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Inhibition of acidic sphingomyelinase reduces established hepatic fibrosis in mice
Author(s) -
Quillin Ralph C.,
Wilson Gregory C.,
Nojima Hiroyuki,
Freeman Christopher M.,
Wang Jiang,
Schuster Rebecca M.,
Blanchard John A.,
Edwards Michael J.,
Gandhi Chandrashekhar R.,
Gulbins Erich,
Lentsch Alex B.
Publication year - 2015
Publication title -
hepatology research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.123
H-Index - 75
eISSN - 1872-034X
pISSN - 1386-6346
DOI - 10.1111/hepr.12352
Subject(s) - cirrhosis , fibrosis , hepatic stellate cell , hepatic fibrosis , transplantation , transforming growth factor , carbon tetrachloride , growth factor , medicine , chemistry , liver transplantation , endocrinology , cancer research , pathology , receptor , organic chemistry
Aim 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 ( CCl 4 ). Methods Mice were treated with CCl 4 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 CCl 4 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. Conclusion The data suggest that ASM is a critical signaling component in HSC for the development of liver fibrosis and represents an important therapeutic target.