Department of Gastroenterological Surgery, Division of Cancer Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan.
Department of Histology and Embryology, Division of Cancer Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan.
J Gastroenterol Hepatol. 2018 Apr;33(4):950-957. doi: 10.1111/jgh.14004. Epub 2018 Jan 26.
Sinusoidal obstruction syndrome (SOS) is a serious drug-induced liver injury. However, the pathophysiology of the disease remains unclear. This study investigated the effects of cilostazol (CZ), a phosphodiesterase III inhibitor, in a monocrotaline (MCT)-induced rat model of SOS.
Male Wistar rats were administrated MCT to induce SOS. Rats were divided into control, MCT, and MCT + CZ groups. In the MCT + CZ group, CZ was administered at 48 h, 24 h, and 30 min prior to and 8 h and 24 h after MCT administration. The MCT group was treated with water instead of CZ. At 48 h after MCT administration, blood and liver samples were collected to assess biochemistry and liver histology. Expression of rat endothelial cell antigen, CD34, CD41, P-selectin, and caspase-3 in the liver were analyzed. Plasminogen activator inhibitor-1 (PAI-1) in hepatocytes was analyzed using western blotting and polymerase chain reaction.
In the MCT group, macroscopic findings showed a dark-red liver surface. Histological findings showed sinusoidal dilatation, coagulative necrosis of hepatocytes, and endothelial damage of the central vein. These changes were attenuated in the MCT + CZ group. Elevated serum transaminase and decreased platelet counts were observed in the MCT + CZ group compared with those in the MCT group. Treatment with CZ reduced MCT-induced damage to the liver sinusoidal endothelial cells, inhibited extravasated platelet aggregation, and suppressed hepatocyte apoptosis around the central vein. CZ attenuated hepatic PAI-1 protein and mRNA levels.
Cilostazol attenuated MCT-induced SOS by preventing damage to liver sinusoidal endothelial cells and extravasated platelet aggregation. Hepatic PAI-1 levels were suppressed with CZ treatment.
窦状隙阻塞综合征（SOS）是一种严重的药物性肝损伤。然而，其发病机制尚不清楚。本研究旨在探讨磷酸二酯酶 III 抑制剂西洛他唑（CZ）在野百合碱（MCT）诱导的 SOS 大鼠模型中的作用。
雄性 Wistar 大鼠给予 MCT 诱导 SOS。大鼠分为对照组、MCT 组和 MCT+CZ 组。MCT+CZ 组于 MCT 给药前 48 h、24 h、30 min 和给药后 8 h、24 h 给予 CZ。MCT 组给予水代替 CZ。MCT 给药后 48 h 采集血样和肝样，检测生物化学和肝组织学变化。分析大鼠肝内皮细胞抗原、CD34、CD41、P-选择素和 caspase-3 的表达。采用 Western blot 和聚合酶链反应检测肝细胞中纤溶酶原激活物抑制剂-1（PAI-1）的表达。
MCT 组大鼠肝脏表面呈暗红色，镜下可见肝窦扩张、肝细胞凝固性坏死和中央静脉内皮损伤。MCT+CZ 组上述改变减轻。与 MCT 组相比，MCT+CZ 组血清转氨酶升高，血小板计数降低。CZ 可减轻 MCT 诱导的肝窦内皮细胞损伤，抑制血小板在窦周隙的聚集，抑制中央静脉周围肝细胞凋亡。CZ 可降低肝 PAI-1 蛋白和 mRNA 水平。
西洛他唑可通过防止肝窦内皮细胞损伤和血小板漏出聚集减轻 MCT 诱导的 SOS，其机制可能与抑制肝 PAI-1 有关。
