Yamaguchi Shohei, Kawanaka Hirofumi, Yoshida Daisuke, Maehara Yoshihiko, Hashizume Makoto
Department of Disaster and Emergency Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Life Sci. 2007 May 8;80(22):2036-44. doi: 10.1016/j.lfs.2007.03.009. Epub 2007 Mar 23.
The enlarged spleen in liver cirrhosis is considered to play a role in the pathogenesis of portal hypertension, but the splenic hemodynamics and molecular mechanisms behind the phenomenon have not been elucidated. The present study aimed to examine the splenic hemodynamics associated with splenic microcirculation and congestion, and to determine the status of the endothelial nitric oxide synthase (eNOS) signaling pathway in the spleen of rats with liver cirrhosis. Liver cirrhosis was induced by bile duct ligation. In rats with bile duct ligation (BDL rats) and control rats, splenic blood flow was measured using a laser Doppler flowmeter, and splenic blood volume was measured using a near-infrared spectrophotometer. The expressions of eNOS and its upstream effectors, Akt, TNF-alpha and VEGF, in the spleen were also determined. Specific splenic blood flow was significantly decreased in BDL rats compared with control rats. Specific splenic blood volume was also decreased in BDL rats, while their total splenic blood volume, especially the deoxygenated volume, was significantly increased. The expressions of phosphorylated and total eNOS, and the eNOS phosphorylation ratio, were all significantly decreased in the spleen of BDL rats. The Akt phosphorylation ratio and TNF-alpha concentration were also decreased in the spleen of BDL rats although the expression of VEGF was increased. These findings suggest that the eNOS signaling pathway is suppressed in the spleen of cirrhotic rats, and may contribute to the measured decreases in specific blood flow and volume in the spleen of liver cirrhosis. Determination of the factors influencing the suppression of eNOS in the spleen may shed light on how liver cirrhosis results in hypodynamic intrasplenic circulation.
肝硬化时脾脏肿大被认为在门静脉高压的发病机制中起作用，但该现象背后的脾脏血流动力学及分子机制尚未阐明。本研究旨在探讨与脾微循环和淤血相关的脾脏血流动力学，并确定肝硬化大鼠脾脏中内皮型一氧化氮合酶（eNOS）信号通路的状态。通过胆管结扎诱导肝硬化。对胆管结扎大鼠（BDL大鼠）和对照大鼠，使用激光多普勒血流仪测量脾血流量，使用近红外分光光度计测量脾血容量。还测定了脾脏中eNOS及其上游效应分子Akt、肿瘤坏死因子-α（TNF-α）和血管内皮生长因子（VEGF）的表达。与对照大鼠相比，BDL大鼠的比脾血流量显著降低。BDL大鼠的比脾血容量也降低，而其总脾血容量，尤其是脱氧血容量显著增加。BDL大鼠脾脏中磷酸化和总eNOS的表达以及eNOS磷酸化率均显著降低。尽管VEGF表达增加，但BDL大鼠脾脏中Akt磷酸化率和TNF-α浓度也降低。这些发现表明，肝硬化大鼠脾脏中的eNOS信号通路受到抑制，可能导致肝硬化大鼠脾脏中测得的比血流量和血容量降低。确定影响脾脏中eNOS抑制的因素可能有助于揭示肝硬化如何导致脾内循环动力不足。
