Liu John Q, Zelko Igor N, Erbynn Efua M, Sham James S K, Folz Rodney J
Division of Pulmonary, Allergy, and Critical Care Medicine, Duke University Medical Center, MSRB 341, Durham, NC 27710, USA.
Am J Physiol Lung Cell Mol Physiol. 2006 Jan;290(1):L2-10. doi: 10.1152/ajplung.00135.2005. Epub 2005 Aug 5.
Chronic exposure to low-O2 tension induces pulmonary arterial hypertension (PAH), which is characterized by vascular remodeling and enhanced vasoreactivity. Recent evidence suggests that reactive oxygen species (ROS) may be involved in both processes. In this study, we critically examine the role superoxide and NADPH oxidase plays in the development of chronic hypoxic PAH. Chronic hypoxia (CH; 10% O2 for 3 wk) caused a significant increase in superoxide production in intrapulmonary arteries (IPA) of wild-type (WT) mice as measured by lucigenin-enhanced chemiluminescence. The CH-induced increase in the generation of ROS was obliterated in NADPH oxidase (gp91phox) knockout (KO) mice, suggesting that NADPH oxidase was the major source of ROS. Importantly, pathological changes associated with CH-induced PAH (mean right ventricular pressure, medial wall thickening of small pulmonary arteries, and right heart hypertrophy) were completely abolished in NADPH oxidase (gp91phox) KO mice. CH potentiated vasoconstrictor responses of isolated IPAs to both 5-hydroxytryptamine (5-HT) and the thromboxane mimetic U-46619. Administration of CuZn superoxide dismutase to isolated IPA significantly reduced CH-enhanced superoxide levels and reduced the CH-enhanced vasoconstriction to 5-HT and U-46619. Additionally, CH-enhanced superoxide production and vasoconstrictor activity seen in WT IPAs were markedly reduced in IPAs isolated from NADPH oxidase (gp91phox) KO mice. These results demonstrate a pivotal role for gp91phox-dependent superoxide production in the pathogenesis of CH-induced PAH.
长期暴露于低氧张力会诱发肺动脉高压（PAH），其特征为血管重塑和血管反应性增强。最近的证据表明，活性氧（ROS）可能参与了这两个过程。在本研究中，我们严格检验了超氧化物和NADPH氧化酶在慢性低氧性PAH发展过程中所起的作用。通过光泽精增强化学发光法测定，慢性低氧（CH；10%氧气，持续3周）导致野生型（WT）小鼠肺内动脉（IPA）中超氧化物生成显著增加。在NADPH氧化酶（gp91phox）基因敲除（KO）小鼠中，CH诱导的ROS生成增加被消除，这表明NADPH氧化酶是ROS的主要来源。重要的是，与CH诱导的PAH相关的病理变化（平均右心室压力、小肺动脉中层壁增厚和右心肥大）在NADPH氧化酶（gp91phox）KO小鼠中完全消失。CH增强了离体IPA对5-羟色胺（5-HT）和血栓素类似物U-46619的血管收缩反应。向离体IPA中施用铜锌超氧化物歧化酶可显著降低CH增强的超氧化物水平，并降低CH增强的对5-HT和U-46619的血管收缩作用。此外，从NADPH氧化酶（gp91phox）KO小鼠分离的IPA中，WT IPA中所见的CH增强的超氧化物生成和血管收缩活性明显降低。这些结果证明了gp91phox依赖性超氧化物生成在CH诱导的PAH发病机制中起关键作用。
