Melatonin possesses potent hepatoprotective properties, but it remains to be elucidated whether melatonin has a therapeutic effect on monocrotaline (MCT)-induced hepatic sinusoidal obstruction syndrome (HSOS). In this study, male Sprague Dawley rats were intraperitoneally injected with melatonin or the same volume of vehicle at 0 and 24 h after MCT intragastric administration. Next, hematoxylin-eosin staining and electron microscopy were performed to evaluate the hepatic sinusoidal injury of rats. Endothelial cell marker RECA-1 was observed by immunohistochemistry. Hepatic oxidative stress was analyzed by detecting malondialdehyde, glutathione S-transferase, and reactive oxygen species. Assessment of liver function was carried out by analysis of serum aspartate aminotransferase, alanine aminotransferase, total bilirubin, and albumin levels. Real-time polymerase chain reaction and Western blot analysis were used to identify liver Sirtuin-3 (SIRT3) and active matrix metallopeptidase 9 (MMP-9) expression. Besides, liver sinusoidal endothelial cells (LSECs) were used for the in vitro functional verification experiment. Specifically, liver histology of the melatonin-treated groups showed that the pathological damages caused by MCT were significantly attenuated, total HSOS scores were decreased, and the elevation of serum hyaluronic acid observed in the model group was also reduced. Moreover, melatonin treatment also improved the survival of rats after partial hepatectomy. Administration of melatonin ameliorated MCT-induced LSECs injury, hepatic oxidative stress, and hepatic dysfunction. Furthermore, melatonin treatment increased SIRT3 expression while attenuating MMP-9 activity in liver tissues. Cell experiment also demonstrated that SIRT3 might mediate the protective effect of melatonin on LSECs. Collectively, our study provided the potential rationale for the application of melatonin for the prevention of MCT-induced HSOS.

通过体内和体外实验方法观察依诺肝素对野百合碱导致肝窦阻塞综合征(HSOS)的治疗及其可能机制。结果显示，野百合碱可导致大鼠HSOS，并降低大鼠肝窦内皮细胞的存活率。与野百合碱比较，依诺肝素治疗可减轻野百合碱所致HSOS大鼠的肝窦阻塞，并可提高肝窦内皮细胞的存活率。此外，野百合碱可使大鼠肝脏、肝窦内皮细胞中Slit2、Robo4蛋白质和mRNA表达下降，但依诺肝素能够上调野百合碱所致HSOS大鼠肝脏、肝窦内皮细胞中Slit2、Robo4蛋白质和mRNA的表达。

目的 探讨沉默信息调节因子1(SIRT1)激动剂白藜芦醇对野百合碱所致肝窦阻塞综合征的保护作用及其可能机制.方法 32只雄性SD大鼠随机分为对照组(8只)、野百合碱组(12只)和白藜芦醇组(12只).野百合碱组和白藜芦醇组给予野百合碱(160 mg/kg)单次灌胃;白藜芦醇组于野百合碱灌胃前1 d开始每天给予白藜芦醇溶液(30 mg/kg)腹腔注射.在给予野百合碱2 d后结束实验.检测血清丙氨酸氨基转移酶(ALT)、天门冬氨酸氨基转移酶(AST)、总胆红素(TBiL)和肝组织内谷胱甘肽(GSH)和丙二醛(MDA)水平,观察肝脏病理变化,应用Western blot检测肝脏SIRT1、HIF-1α和VEGF蛋白的表达水平.结果 与对照组相比,野百合碱组大鼠单次灌胃后血清ALT、AST及TBiL有所升高(均P<0.01),肝脏GSH水平降低(P<0.01)、MDA升高(P<0.01);肝脏组织病理学可见肝细胞排列紊乱,并出现变性、坏死,肝窦淤血扩张,中央静脉内皮损伤,SIRT1蛋白的表达水平降低(P<0.01),HIF-1α和VEGF蛋白的表达水平有所增加(P<0.01).使用白藜芦醇干预后,血清ALT、AST、TBiL指标下降(P<0.05或P<0.01),肝脏GSH水平升高(P<0.01)、MDA降低(P<0.01),并可以抑制野百合碱引起的肝脏病理损伤,SIRT1蛋白的表达水平升高(P<0.01),HIF-1α和VEGF蛋白表达下调(P<0.01).结论 白藜芦醇可以改善野百合碱引起的大鼠肝窦阻塞综合征,其机制与激活SIRT1、抑制HIF-1α/VEGF信号通路及抗氧化应激相关.

目的 探讨Slit2/Robo4/Rho信号通路在野百合碱(MCT)导致肝窦阻塞综合征(HSOS)发病中的作用.方法 34只SD大鼠随机分为正常对照组和实验组.实验组大鼠给予MCT灌胃(160 mg/kg),分批在造模后第1、2、4天随机处死,正常组第4天处死.收集血液样本和肝组织,测定血清丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)水平,观察肝脏组织学变化,测定肝脏α-平滑肌肌动蛋白(α-SMA)表达和肝脏Slit2、Robo4、RhoA、Racl、Cdc42及基质金属蛋白酶(MMP)-2、MMP-9 mRNA和蛋白的变化.结果 大鼠单次灌胃MCT(160 mg/kg)后,第1天肝窦淤血、肝细胞变性和中央静脉内皮损伤;第2天肝窦淤血扩张明显;第4天肝脏病变加重,可见窦周纤维化.与正常对照组比较,各实验组大鼠的肝指数均升高(P＜0.05),实验组第2、4天AST水平升高(P＜0.01),第2天ALT升高(P＜0.01).与正常对照比较,各实验组α-SMA表达升高(P＜0.01).各实验组Slit2和Robo4 mRNA和蛋白低于正常对照(P＜0.01),随着给药时间的延长,实验组大鼠Slit2和Robo4 mRNA和蛋白的表达逐渐降低(P＜0.05);而各实验组RhoA、Rac1、Cdc42及MMP-2、MMP-9 mRNA和蛋白高于正常对照组,且表达逐步升高(P＜0.05).结论 单次MCT摄入可使大鼠发生HSOS,且肝损伤呈进行性加重.Slit2/Robo4/Rho信号通路、肝星状细胞激活及MMP-2、MMP-9升高可能是MCT致HSOS发生的重要作用机制之一.