Cilostazol attenuates hepatic stellate cell activation and protects mice against carbon tetrachloride-induced liver fibrosis.
Cilostazol attenuates hepatic stellate cell activation and protects mice against carbon tetrachloride-induced liver fibrosis.
复制标题
西洛他唑减弱肝星状细胞活化并保护小鼠免受四氯化碳诱导的肝纤维化。
作者：
Saito S;Hata K;Iwaisako K;Yanagida A;Takeiri M;Tanaka H;Kageyama S;Hirao H;Ikeda K;Asagiri M;Uemoto S
目的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，已被证明在实验性非酒精性脂肪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功效仍然难以捉摸。方法将雄性C57BL/6J小鼠分为五组：正常饮食喂养的小鼠（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）。喂养两周后，第 2-5 组每周两次腹腔注射四氯化碳 (CCl4)，持续 6 周，而第 1 组仅用载体治疗。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）、库普弗细胞和补充西洛他唑的肝细胞进行了体外研究。结果天狼星红染色显示，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％）小于对照组。第2组（分别为3.17±0.67%，P<0.05和P<0.001）。体外研究显示西洛他唑剂量依赖性抑制HSC活化（通过形态变化、细胞增殖和HSC活化标志物的表达进行评估），表明西洛他唑的治疗效果是通过其对HSC的直接作用介导的。结论西洛他唑可以缓解CCl4 诱导的体内肝纤维发生，可能至少部分是由于其直接抑制 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。
AimLiver 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.MethodsMale 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 vitrostudies were conducted using primary hepatic stellate cells (HSC), Kupffer cells and hepatocytes with cilostazol supplementation.ResultsSirius 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 andP< 0.001, respectively).In vitrostudies 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.ConclusionCilostazol could alleviate CCl4‐induced hepatic fibrogenesisin 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.