Premium
Cilostazol attenuates hepatic stellate cell activation and protects mice against carbon tetrachloride‐induced liver fibrosis
Author(s) -
Saito Shunichi,
Hata Koichiro,
Iwaisako Keiko,
Yanagida Atsuko,
Takeiri Masatoshi,
Tanaka Hirokazu,
Kageyama Shoichi,
Hirao Hirofumi,
Ikeda Kazuo,
Asagiri Masataka,
Uemoto Shinji
Publication year - 2014
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.12140
Subject(s) - cilostazol , hepatic stellate cell , cirrhosis , carbon tetrachloride , medicine , hepatic fibrosis , fatty liver , pharmacology , in vivo , chemistry , endocrinology , biology , aspirin , microbiology and biotechnology , disease , organic chemistry
Aim Liver fibrosis is a common pathway leading to cirrhosis. Cilostazol, a clinically available oral phosphodiesterase‐3 inhibitor, has been shown to have antifibrotic potential in experimental non‐alcoholic fatty liver disease. However, the detailed mechanisms of the antifibrotic effect and its efficacy in a different experimental model remain elusive. Methods Male C57BL/6J mice were assigned to five groups: mice fed a normal diet (groups 1 and 2); 0.1% or 0.3% cilostazol‐containing diet (groups 3 and 4, respectively); and 0.125% clopidogrel‐containing diet (group 5). Two weeks after feeding, groups 2–5 were intraperitoneally administered carbon tetrachloride ( CCl 4 ) twice a week for 6 weeks, while group 1 was treated with the vehicle alone. To investigate the effects of cilostazol on hepatic cells, in vitro studies were conducted using primary hepatic stellate cells ( HSC ), Kupffer cells and hepatocytes with cilostazol supplementation. Results Sirius red staining revealed that groups 3 and 4 exhibited a lesser fibrotic area (2.49 ± 0.43% and 2.31 ± 0.30%, respectively) than group 2 (3.17 ± 0.67%, P < 0.05 and P < 0.001, respectively). In vitro studies showed cilostazol dose‐dependently suppressed HSC activation (assessed by morphological change, cell proliferation, and the expression of HSC activation markers), suggesting the therapeutic effect of cilostazol is mediated by its direct action on HSC . Conclusion Cilostazol could alleviate CCl 4 ‐induced hepatic fibrogenesis in vivo , presumably due, at least partly, to its direct effect to suppress HSC activation. Given its clinical availability and safety, it may be a novel therapeutic intervention for chronic liver diseases.