Dweik R A, Laskowski D, Abu-Soud H M, Kaneko F, Hutte R, Stuehr D J, Erzurum S C
Pulmonary and Critical Care Medicine, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
J Clin Invest. 1998 Feb 1;101(3):660-6. doi: 10.1172/JCI1378.
In this study, we show that oxygen regulates nitric oxide (NO) levels through effects on NO synthase (NOS) enzyme kinetics. Initially, NO synthesis in the static lung was measured in bronchiolar gases during an expiratory breath-hold in normal individuals. NO accumulated exponentially to a plateau, indicating balance between NO production and consumption in the lung. Detection of NO2-, NO3-, and S-nitrosothiols in lung epithelial lining fluids confirmed NO consumption by chemical reactions in the lung. Interestingly, alveolar gas NO (estimated from bronchiolar gases at end-expiration) was near zero, suggesting NO in exhaled gases is not derived from circulatory/systemic sources. Dynamic NO levels during tidal breathing in different airway regions (mouth, trachea, bronchus, and bronchiole) were similar. However, in individuals breathing varying levels of inspired oxygen, dynamic NO levels were notably dependent on O2 concentration in the hypoxic range (KmO2 190 microM). Purified NOS type II enzyme activity in vitro was similarly dependent on molecular oxygen levels (KmO2 135 microM), revealing a means by which oxygen concentration affects NO levels in vivo. Based upon these results, we propose that NOS II is a mediator of the vascular response to oxygen in the lung, because its KmO2 allows generation of NO in proportion to the inspired oxygen concentration throughout the physiologic range.
在本研究中，我们表明氧气通过影响一氧化氮合酶（NOS）的酶动力学来调节一氧化氮（NO）水平。最初，在正常个体呼气屏气期间，于细支气管气体中测量静态肺中的NO合成。NO呈指数级积累至平台期，表明肺中NO生成与消耗之间达到平衡。肺上皮衬液中NO2-、NO3-和S-亚硝基硫醇的检测证实了肺中化学反应对NO的消耗。有趣的是，肺泡气NO（根据呼气末细支气管气体估算）接近零，这表明呼出气体中的NO并非源自循环/全身来源。不同气道区域（口腔、气管、支气管和细支气管）在潮式呼吸期间的动态NO水平相似。然而，在吸入不同氧含量的个体中，动态NO水平在低氧范围内（KmO2 190 microM）显著依赖于O2浓度。体外纯化的II型NOS酶活性同样依赖于分子氧水平（KmO2 135 microM），揭示了氧浓度影响体内NO水平的一种方式。基于这些结果，我们提出NOS II是肺血管对氧气反应的介质，因为其KmO2允许在整个生理范围内按吸入氧浓度比例生成NO。
