Soluble guanylate cyclase as an alternative target for bronchodilator therapy in asthma
Soluble guanylate cyclase as an alternative target for bronchodilator therapy in asthma
复制标题
DOI：
10.1073/pnas.1524398113
复制
发表时间：
2016-04-26
影响因子：
11.1
通讯作者：
Stuehr, Dennis J.
中科院分区：
文献类型：
--
作者：
Ghosh, Arnab;Koziol-White, Cynthia J.;Stuehr, Dennis J.
哮喘的定义是气道炎症和高反应性，并导致全球范围内的发病率和死亡率。虽然支气管扩张是治疗的基础，但随着哮喘严重程度的恶化，目前的支气管扩张剂变得无效。我们研究了另一种途径，涉及激活气道平滑肌酶，可溶性鸟苷酸环化酶（sGC）。通过其天然刺激剂一氧化氮（NO）或通过药理学sGC激动剂BAY 41-2272和BAY 60-2770激活sGC，触发正常人肺切片和小鼠气道中的支气管扩张。BAY 41-2272和BAY 60-2770都逆转了过敏性哮喘小鼠的气道高反应性，并恢复了正常的肺功能。来自小鼠哮喘肺的sGC显示出氧化损伤的三个标志，使其对NO不敏感，并且当给予慢性NO暴露以模拟哮喘肺中的高NO时，在人肺切片或人气道平滑肌细胞中发生与sGC相同的变化。我们的研究结果表明哮喘中的过敏性炎症可能如何阻碍基于NO的支气管扩张，并揭示尽管存在这种损失，药理学sGC激动剂仍然可以实现支气管扩张。
Asthma is defined by airway inflammation and hyperresponsiveness, and contributes to morbidity and mortality worldwide. Although bronchodilation is a cornerstone of treatment, current bronchodilators become ineffective with worsening asthma severity. We investigated an alternative pathway that involves activating the airway smooth muscle enzyme, soluble guanylate cyclase (sGC). Activating sGC by its natural stimulant nitric oxide (NO), or by pharmacologic sGC agonists BAY 41-2272 and BAY 60-2770, triggered bronchodilation in normal human lung slices and in mouse airways. Both BAY 41-2272 and BAY 60-2770 reversed airway hyperresponsiveness in mice with allergic asthma and restored normal lung function. The sGC from mouse asthmatic lungs displayed three hallmarks of oxidative damage that render it NO-insensitive, and identical changes to sGC occurred in human lung slices or in human airway smooth muscle cells when given chronic NO exposure to mimic the high NO in asthmatic lung. Our findings show how allergic inflammation in asthma may impede NO-based bronchodilation, and reveal that pharmacologic sGC agonists can achieve bronchodilation despite this loss.