Hasegawa Jo, Wagner Klaus F, Karp Dörte, Li Dechun, Shibata Junpei, Heringlake Matthias, Bahlmann Ludger, Depping Reinhard, Fandrey Joachim, Schmucker Peter, Uhlig Stefan
Department of Anesthesiology and Critical Care Medicine, University of Lübeck, Lübeck, Germany.
Am J Respir Crit Care Med. 2004 Apr 1;169(7):829-35. doi: 10.1164/rccm.200308-1154OC. Epub 2003 Dec 30.
Pulmonary vascular remodeling during chronic hypoxia may be the result of either oxygen deprivation or erythrocytosis. To separate experimentally the effects of hypoxia and erythrocytosis, we analyzed transgenic mice that constitutively overexpress the human erythropoietin gene in an oxygen-independent manner. These mice are characterized by polycythemia but have normal blood pressure, heart rate, and cardiac output. In transgenic mice, pulmonary artery pressure (PAP) was increased in vivo but was reduced in blood-free perfused lungs. The thromboxane receptor agonist U46619 caused a smaller rise in PAP in isolated transgenic lungs than in lungs from wild-type mice. The transgenic pulmonary vasculature was characterized by elevated prostacyclin production, stronger endothelial nitric oxide synthase expression, and reduced pulmonary vascular smooth muscle thickness. The fact that transgenic polycythemic mice have marked pulmonary hypertension in vivo but not in vitro suggests that their pulmonary hypertension is due to the increased blood viscosity, thus supporting an independent role of polycythemia in the development of pulmonary hypertension. In addition, our findings indicate that the lungs of transgenic animals adapt to the high PAP by elevated synthesis of vasodilators and reduced vascular smooth muscle thickness that tend to reduce vascular tone and vascular responsiveness.
慢性缺氧期间的肺血管重塑可能是缺氧或红细胞增多症的结果。为了通过实验区分缺氧和红细胞增多症的影响，我们分析了以氧非依赖方式组成性过表达人促红细胞生成素基因的转基因小鼠。这些小鼠的特征是红细胞增多，但血压、心率和心输出量正常。在转基因小鼠中，体内肺动脉压（PAP）升高，但在无血灌注肺中降低。血栓素受体激动剂U46619在分离的转基因肺中引起的PAP升高幅度小于野生型小鼠肺中的升高幅度。转基因肺血管系统的特征是前列环素生成增加、内皮型一氧化氮合酶表达增强以及肺血管平滑肌厚度减小。转基因红细胞增多症小鼠在体内而非体外出现明显肺动脉高压这一事实表明，它们的肺动脉高压是由于血液粘度增加所致，从而支持了红细胞增多症在肺动脉高压发展中的独立作用。此外，我们的研究结果表明，转基因动物的肺通过增加血管舒张剂的合成和减小血管平滑肌厚度来适应高PAP，这往往会降低血管张力和血管反应性。
