The relationship between endotoxemia and hepatic endocannabinoids in cirrhotic rats with portal hypertension
The relationship between endotoxemia and hepatic endocannabinoids in cirrhotic rats with portal hypertension
复制标题
DOI：
10.1016/j.jhep.2010.09.026
复制
发表时间：
2011-06-01
影响因子：
25.7
通讯作者：
Lee, Shou-Dong
中科院分区：
文献类型：
--
作者：
Lin, Han-Chieh;Yang, Ying-Ying;Lee, Shou-Dong
背景与目的：肝硬变的特征是内毒素血症和肝内阻力增加，这是由肝纤维化和内皮功能障碍以及包括大麻素受体(CB1和CB2)在内的内源性大麻素系统激活引起的。内毒素除了促进肝纤维化的形成外，还可诱导循环中的内源性大麻素的释放，从而导致肝硬变时的门脉高压。方法：测定平均动脉压、心脏指数、全身血管阻力、肠系膜上动脉血流和阻力、PVP、血浆内毒素和肝肿瘤坏死因子-α(TNF-α)、内酰胺和2-花生四烯基甘油、肝组织大麻素受体、内皮型一氧化氮合酶(ENOS)、磷酸化eNOS、Akt、磷酸化-Akt和血栓素合成酶(TXS)、基质金属酶-2(MMP2)、金属蛋白酶组织抑制因子-2(TIMP-2)、肝纤维化，白细胞浸润。结果：BDL-CIPO组大鼠血浆内毒素水平、肝组织肿瘤坏死因子α、α-烷胺和2-花生四烯基甘油含量、肝组织TXS、MMP2、TIMP-2表达、肝纤维化程度、肝内白细胞浸润、肝内动脉压和肝内阻力均明显低于BDL-V组。相反，BDL-Cipro大鼠的全身血管阻力、eNOS和Akt磷酸化水平显著高于BDL-V大鼠。结论：环丙沙星可抑制肝硬变大鼠的内毒素血症和肝内大麻素系统，从而改善高动力循环，降低肝内阻力，从而预防肝纤维化和内皮功能障碍。(C)2010年欧洲肝脏研究协会。爱思唯尔出版，版权所有。
Background & Aims: Cirrhosis is characterized by endotoxemia and increased intrahepatic resistance, which is caused by hepatic fibrosis and endothelial dysfunction, as well as the activated endocannabinoids system, including cannabinoid (CB1 and CB2) receptors. Besides accelerating hepatic fibrogenesis, endotoxins induce the release of circulating endocannabinoids and portal hypertension in cirrhosis. This study examines how suppression of endotoxemia by antibiotics affects intrahepatic resistance and the hepatic endocannabinoid system in bile-duct-ligated (BDL) rats.Methods: Measurements were performed that included: mean arterial pressure, cardiac index (Cl), systemic vascular resistance, superior mesenteric arterial blood flow and resistance, PVP, plasma endotoxin and hepatic tumor necrosis factor-alpha (TNF alpha), anandamide and 2-arachidonylglycerol, hepatic expression of cannabinoid receptors, endothelial nitric oxide synthase (eNOS), phospho-eNOS, Akt, phospho-Akt and thromboxane synthase (TXS), matrix metalloproteinase-2 (MMP-2), tissue inhibitor of metalloproteinase-2 (TIMP-2), hepatic fibrosis, and leukocyte infiltration. Hepatic endothelial dysfunction was evaluated in BDL rats receiving vehicle (BDL-V) or 2-weeks of ciprofloxacin (BDL-cipro).Results: Plasma endotoxin and hepatic TNF alpha, anandamide and 2-arachidonylglycerol, expression of TXS, MMP-2, TIMP-2, hepatic fibrosis and infiltration of hepatic leukocytes, Cl, PVP and intrahepatic resistance were significantly lower in BDL-cipro than in BDL-V rats. Conversely, systemic vascular resistance, eNOS and Akt phosphorylation were significantly higher in BDL-cipro than in BDL-V rats. Improvement of hepatic endothelial dysfunction was associated with lower expression of hepatic CB(1)and a higher expression of hepatic CB2 in BDL-cipro rats.Conclusions: In cirrhotic rats, ciprofloxacin suppressed endotoxemia and the hepatic endocannabinoid system thus ameliorating hyperdynamic circulation and decreased intrahepatic resistance by preventing hepatic fibrogenesis and endothelial dysfunction. (C) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.