{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T01:00:30Z","timestamp":1790470830481,"version":"4.1.0"},"reference-count":39,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2014,6,4]],"date-time":"2014-06-04T00:00:00Z","timestamp":1401840000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes Health","doi-asserted-by":"crossref","award":["DK56029"],"award-info":[{"award-number":["DK56029"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes Health","doi-asserted-by":"crossref","award":["AG025881"],"award-info":[{"award-number":["AG025881"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes Health","doi-asserted-by":"crossref","award":["AA020846"],"award-info":[{"award-number":["AA020846"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"VA Merit Review","award":["BX001174"],"award-info":[{"award-number":["BX001174"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Hepatology Research"],"published-print":{"date-parts":[[2015,3]]},"abstract":"Aim<\/jats:title>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<\/jats:styled-content>) 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<\/jats:styled-content>) has been shown to be involved in HSC<\/jats:styled-content> activation. In the present study we investigated whether treatment with the ASM<\/jats:styled-content> inhibitor, amitriptyline (TCA<\/jats:styled-content>), could prevent and\/or reverse fibrosis induced in mice by carbon tetrachloride (CCl4<\/jats:sub><\/jats:roman><\/jats:styled-content>).<\/jats:p><\/jats:sec>Methods<\/jats:title>Mice were treated with CCl4<\/jats:sub><\/jats:roman><\/jats:styled-content> for 8\u2009weeks to induce fibrosis. Concurrently, mice received drinking water with or without 180\u2009mg\/L TCA<\/jats:styled-content>.<\/jats:p><\/jats:sec>Results<\/jats:title>Mice receiving TCA<\/jats:styled-content> in the water had decreased hepatic collagen deposition and reduced liver mRNA<\/jats:styled-content> expression of the fibrogenic mediators, transforming growth factor (TGF<\/jats:styled-content>)\u2010\u03b21, tissue inhibitor of matrix metalloproteinase\u20101, collagen and tumor necrosis factor\u2010\u03b1. TCA<\/jats:styled-content> treatment also reduced HSC<\/jats:styled-content> activation determined by \u03b1\u2010smooth muscle actin staining. In a separate set of experiments, mice were treated with CCl4<\/jats:sub><\/jats:roman><\/jats:styled-content> for 5\u2009weeks prior to treatment with TCA<\/jats:styled-content>, to test whether TCA<\/jats:styled-content> had any effect on established fibrosis. Remarkably, in mice with established fibrosis, treatment with TCA<\/jats:styled-content> significantly reduced collagen deposition, HSC<\/jats:styled-content> activation, and prevented portal hypertension and improved hepatic architecture. Treatment of isolated HSC<\/jats:styled-content>\u2005in vitro<\/jats:italic> with TCA<\/jats:styled-content> completely inhibited TGF<\/jats:styled-content>\u2010\u03b21\u2010induced collagen expression and platelet\u2010derived growth factor\u2010\u03b2\u2010\u03b2\u2010induced proliferation.<\/jats:p><\/jats:sec>Conclusion<\/jats:title>The data suggest that ASM<\/jats:styled-content> is a critical signaling component in HSC<\/jats:styled-content> for the development of liver fibrosis and represents an important therapeutic target.<\/jats:p><\/jats:sec>","DOI":"10.1111\/hepr.12352","type":"journal-article","created":{"date-parts":[[2014,5,5]],"date-time":"2014-05-05T02:10:58Z","timestamp":1399255858000},"page":"305-314","source":"Crossref","is-referenced-by-count":23,"title":["Inhibition of acidic sphingomyelinase reduces established hepatic fibrosis in mice"],"prefix":"10.1111","volume":"45","author":[{"suffix":"III","given":"Ralph C.","family":"Quillin","sequence":"first","affiliation":[{"name":"Department of Surgery Laboratory Medicine University of Cincinnati College of Medicine Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory C.","family":"Wilson","sequence":"additional","affiliation":[{"name":"Department of Surgery Laboratory Medicine University of Cincinnati College of Medicine Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Nojima","sequence":"additional","affiliation":[{"name":"Department of Surgery Laboratory Medicine University of Cincinnati College of Medicine Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher M.","family":"Freeman","sequence":"additional","affiliation":[{"name":"Department of Surgery Laboratory Medicine University of Cincinnati College of Medicine Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pathology Laboratory Medicine University of Cincinnati College of Medicine Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca M.","family":"Schuster","sequence":"additional","affiliation":[{"name":"Department of Surgery Laboratory Medicine University of Cincinnati College of Medicine Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John A.","family":"Blanchard","sequence":"additional","affiliation":[{"name":"Department of Surgery Laboratory Medicine University of Cincinnati College of Medicine Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Edwards","sequence":"additional","affiliation":[{"name":"Department of Surgery Laboratory Medicine University of Cincinnati College of Medicine Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandrashekhar R.","family":"Gandhi","sequence":"additional","affiliation":[{"name":"Department of Surgery Laboratory Medicine University of Cincinnati College of Medicine Cincinnati Ohio USA"},{"name":"Division of Gastroenterology, Hepatology and Nutrition Cincinnati Children's Hospital Medical Center Cincinnati Ohio USA"},{"name":"Veterans Administration Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erich","family":"Gulbins","sequence":"additional","affiliation":[{"name":"Department of Surgery Laboratory Medicine University of Cincinnati College of Medicine Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex B.","family":"Lentsch","sequence":"additional","affiliation":[{"name":"Department of Surgery Laboratory Medicine University of Cincinnati College of Medicine Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,6,4]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI24282"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-6143.2004.00703.x"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-6143.2010.03037.x"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/ajt.12021"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-011110-130246"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1586\/17474124.2.6.803"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40139-013-0018-7"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1159\/000315101"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2005.09.001"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.2174\/1874312901206010123"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2329"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.73.011303.073731"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/112_0507"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2012.04.005"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.08-108043"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2011.07.010"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-7091-1368-4_9"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2010.11.038"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2010.091257"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1159\/000350071"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm1539"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2009.09.008"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm1748"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1159\/000185482"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.20701"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1200819"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1102460"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2013.03.032"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0011256"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1097\/00000658-197004000-00007"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.3780384"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/gt.2008.93"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.45.27179"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.1998.275.5.L843"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.20.5.1507-1514.2000"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.17.10299"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M008340200"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.1840380414"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1002\/1097-4652(2001)9999:9999<00::AID-JCP1059>3.0.CO;2-S"}],"container-title":["Hepatology Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fhepr.12352","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/hepr.12352","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,3]],"date-time":"2023-10-03T04:22:11Z","timestamp":1696306931000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/hepr.12352"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,6,4]]},"references-count":39,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2015,3]]}},"alternative-id":["10.1111\/hepr.12352"],"URL":"https:\/\/doi.org\/10.1111\/hepr.12352","archive":["Portico"],"relation":{},"ISSN":["1386-6346","1872-034X"],"issn-type":[{"value":"1386-6346","type":"print"},{"value":"1872-034X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,6,4]]}}}