Saito Shunichi, Hata Koichiro, Iwaisako Keiko, Yanagida Atsuko, Takeiri Masatoshi, Tanaka Hirokazu, Kageyama Shoichi, Hirao Hirofumi, Ikeda Kazuo, Asagiri Masataka, Uemoto Shinji
Department of Surgery, Division of Hepato-Pancreato-Biliary Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
Hepatol Res. 2014 Apr;44(4):460-73. doi: 10.1111/hepr.12140. Epub 2013 Jun 30.
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.
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 (CCl4 ) 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.
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.
Cilostazol could alleviate CCl4 -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.
肝纤维化是导致肝硬化的常见途径。西洛他唑是一种临床可用的口服磷酸二酯酶-3抑制剂，已显示在实验性非酒精性脂肪性肝病中具有抗纤维化潜力。然而，抗纤维化作用的详细机制及其在不同实验模型中的疗效仍不清楚。
将雄性C57BL/6J小鼠分为五组：喂食正常饮食的小鼠（第1组和第2组）；含0.1%或0.3%西洛他唑的饮食（分别为第3组和第4组）；以及含0.125%氯吡格雷的饮食（第5组）。喂食两周后，第2 - 5组小鼠每周两次腹腔注射四氯化碳（CCl4），持续6周，而第1组仅用赋形剂处理。为了研究西洛他唑对肝细胞的影响，使用原代肝星状细胞（HSC）、库普弗细胞和补充了西洛他唑的肝细胞进行体外研究。
天狼星红染色显示，第3组和第4组的纤维化面积（分别为2.49±0.43%和2.31±0.30%）小于第2组（3.17±0.67%，P分别＜0.05和P＜0.001）。体外研究表明，西洛他唑剂量依赖性地抑制HSC活化（通过形态变化、细胞增殖和HSC活化标志物的表达评估），提示西洛他唑的治疗作用是通过其对HSC的直接作用介导的。
西洛他唑可减轻CCl4诱导的体内肝纤维化，推测至少部分原因是其直接抑制HSC活化的作用。鉴于其临床可用性和安全性，它可能是慢性肝病的一种新型治疗干预措施。
