The Role of Soluble Guanylyl Cyclase in Chronic Obstructive Pulmonary Disease
The Role of Soluble Guanylyl Cyclase in Chronic Obstructive Pulmonary Disease
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DOI：
10.1164/rccm.201210-1884oc
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发表时间：
2013-10-01
影响因子：
24.7
通讯作者：
Brusselle, Guy G.
中科院分区：
文献类型：
--
作者：
Glynos, Constantinos;Dupont, Lisa L.;Brusselle, Guy G.
基本原理：可溶性鸟苷酸环化酶（sGC）是一种环鸟苷5 '-单磷酸生成酶，在哮喘和急性肺损伤动物模型中调节平滑肌张力并发挥抗炎作用。在慢性阻塞性肺疾病（COPD）中，主要由香烟烟雾（CS）引起，肺部炎症持续存在，平滑肌张力保持升高，尽管大量的一氧化氮可以激活sGC.目的：确定sGC在COPD患者和COPD小鼠模型中的表达和功能。在从不吸烟者、无气流限制的吸烟者和COPD患者的肺中以及在CS暴露3天、4周和24周后的C57 BL/6小鼠中检查sGC α 1、α 2和β 1亚基的表达。sGC的功能作用进行了研究，在体内通过测量支气管对5-羟色胺在小鼠中使用遗传和药理学approaches. Measures和主要结果：sGC的肺表达，无论是在mRNA和蛋白质水平，在吸烟者没有气流限制，并在COPD患者，并与疾病的严重程度（FEV1%）。在小鼠中，暴露于CS降低了sGC、环鸟苷5 '-单磷酸水平和蛋白激酶G活性。暴露于CS的sGC α 1（-/-）小鼠表现出对5-羟色胺的支气管高反应性。BAY 58-2667对sGC的激活恢复了sGC信号传导，并减弱了CS暴露小鼠的支气管高反应性。结论：CS暴露导致sGC下调可能与COPD气流受限有关。
Rationale: Soluble guanylyl cyclase (sGC), a cyclic guanosine 5'-monophosphate-generating enzyme, regulates smooth muscle tone and exerts antiinflammatory effects in animal models of asthma and acute lung injury. In chronic obstructive pulmonary disease (COPD), primarily caused by cigarette smoke (CS), lung inflammation persists and smooth muscle tone remains elevated, despite ample amounts of nitric oxide that could activate sGC.Objectives: To determine the expression and function of sGC in patients with COPD and in a murine model of COPD.Methods: Expression of sGC alpha 1, alpha 2, and beta 1 subunits was examined in lungs of never-smokers, smokers without airflow limitation, and patients with COPD; and in C57BL/6 mice after 3 days, 4 weeks, and 24 weeks of CS exposure. The functional role of sGC was investigated in vivo by measuring bronchial responsiveness to serotonin in mice using genetic and pharmacologic approaches.Measurements and Main Results: Pulmonary expression of sGC, both at mRNA and protein level, was decreased in smokers without airflow limitation and in patients with COPD, and correlated with disease severity (FEV1%). In mice, exposure to CS reduced sGC, cyclic guanosine 5'-monophosphate levels, and protein kinase G activity. sGC alpha 1(-/-) mice exposed to CS exhibited bronchial hyperresponsiveness to serotonin. Activation of sGC by BAY 58-2667 restored the sGC signaling and attenuated bronchial hyperresponsiveness in CS-exposed mice.Conclusions: Down-regulation of sGC because of CS exposure might contribute to airflow limitation in COPD.