Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taiwan.
J Hepatol. 2011 Jun;54(6):1145-53. doi: 10.1016/j.jhep.2010.09.026. Epub 2010 Nov 12.
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 (CB(1) and CB(2)) 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.
Measurements were performed that included: mean arterial pressure, cardiac index (CI), systemic vascular resistance, superior mesenteric arterial blood flow and resistance, PVP, plasma endotoxin and hepatic tumor necrosis factor-α (TNFα), 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).
Plasma endotoxin and hepatic TNFα, anandamide and 2-arachidonylglycerol, expression of TXS, MMP-2, TIMP-2, hepatic fibrosis and infiltration of hepatic leukocytes, CI, 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 CB(2) in BDL-cipro rats.
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.
肝硬化的特征为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激活的内源性大麻素系统（包括大麻素（CB1 和 CB2）受体）引起的。除了加速肝纤维化外，内毒素还会在肝硬化中诱导循环内源性大麻素的释放和门脉高压。本研究旨在探讨抗生素抑制内毒素血症对胆管结扎（BDL）大鼠肝内阻力和肝内内源性大麻素系统的影响。
进行了以下测量：平均动脉压、心指数（CI）、全身血管阻力、肠系膜上动脉血流和阻力、门静脉压力（PVP）、血浆内毒素和肝肿瘤坏死因子-α（TNFα）、花生四烯酸乙醇胺和 2-花生四烯酰甘油、肝内大麻素受体、内皮型一氧化氮合酶（eNOS）、磷酸化 eNOS、Akt、磷酸化 Akt 和血栓素合酶（TXS）、基质金属蛋白酶-2（MMP-2）、组织抑制剂金属蛋白酶-2（TIMP-2）、肝纤维化和白细胞浸润的表达。在接受载体（BDL-V）或 2 周环丙沙星（BDL-cipro）的 BDL 大鼠中评估肝内皮功能障碍。
与 BDL-V 大鼠相比，BDL-cipro 大鼠的血浆内毒素和肝 TNFα、花生四烯酸乙醇胺和 2-花生四烯酰甘油、TXS、MMP-2、TIMP-2、肝纤维化和肝白细胞浸润、CI、PVP 和肝内阻力显著降低。相反，BDL-cipro 大鼠的全身血管阻力、eNOS 和 Akt 磷酸化显著高于 BDL-V 大鼠。BDL-cipro 大鼠肝内内皮功能障碍的改善与肝 CB1 表达降低和肝 CB2 表达升高有关。
在肝硬化大鼠中，环丙沙星抑制内毒素血症和肝内内源性大麻素系统，从而通过预防肝纤维化和内皮功能障碍来改善高动力循环和降低肝内阻力。
