Expression of nitric oxide synthase-2 in the lungs decreases airway resistance and responsiveness
Expression of nitric oxide synthase-2 in the lungs decreases airway resistance and responsiveness
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DOI：
10.1152/japplphysiol.01389.2003
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发表时间：
2004-07-01
影响因子：
3.3
通讯作者：
Silverman, ES
中科院分区：
文献类型：
--
作者：
Hjoberg, J;Shore, S;Silverman, ES
哮喘患者呼出的空气中一氧化氮水平升高。为了探索它的作用，我们已经开发了一个可调节的转基因小鼠能够过表达诱导型一氧化氮合酶在肺特异性的方式。CC 10-rtTA-NOS-2小鼠含有两种转基因，即Clara细胞蛋白启动子控制下的反向四环素反式激活因子和四环素操纵子控制下的小鼠一氧化氮合酶-2（NOS-2）编码区。向CC 10-rtTA-NOS-2小鼠的饮用水中添加多西环素导致一氧化氮合酶-2的增加，其主要局限于气道上皮。在最初的24小时内，呼出的一氧化氮的分数从大约十亿分之十增加到大约十亿分之二十。CC 10-rtTA-NOS-2小鼠（有或无强力霉素）与野生型小鼠在肺组织学、支气管肺泡蛋白、总细胞计数或计数差异方面无明显差异。然而，具有多西环素的CC 10-rtTA-NOS-2小鼠的气道阻力低于不具有多西环素的CC 10-rtTA-NOS-2小鼠或具有多西环素的野生型小鼠。此外，与其他组相比，多西环素处理的CC 10-rtTANOS-2小鼠对乙酰甲胆碱反应迟钝。这些数据表明，气道中一氧化氮的增加本身没有促炎作用，可能对肺功能有有益的影响。
Individuals with asthma have increased levels of nitric oxide in their exhaled air. To explore its role, we have developed a regulatable transgenic mouse capable of overexpressing inducible nitric oxide synthase in a lung-specific fashion. The CC10-rtTA-NOS-2 mouse contains two transgenes, a reverse tetracycline transactivator under the control of the Clara cell protein promoter and the mouse nitric oxide synthase-2 (NOS-2) coding region under control of a tetracycline operator. Addition of doxycycline to the drinking water of CC10-rtTA-NOS-2 mice causes an increase in nitric oxide synthase-2 that is largely confined to the airway epithelium. The fraction of expired nitric oxide increases over the first 24 h from similar to 10 parts per billion to a plateau of similar to20 parts per billion. There were no obvious differences between CC10-rtTA-NOS-2 mice, with or without doxycycline, and wild-type mice in lung histology, bronchoalveolar protein, total cell count, or count differentials. However, airway resistance was lower in CC10-rtTA-NOS-2 mice with doxycycline than in CC10-rtTA-N0S-2 mice without doxycycline or wild-type mice with doxycycline. Moreover, doxycycline-treated CC10-rtTANOS-2 mice were hyporesponsive to methacholine compared with other groups. These data suggest that increased nitric oxide in the airways has no proinflammatory effects per se and may have beneficial effects on pulmonary function.