Absence of muscarinic cholinergic airway responses in mice deficient in the cyclic nucleotide phosphodiesterase PDE4D
Absence of muscarinic cholinergic airway responses in mice deficient in the cyclic nucleotide phosphodiesterase PDE4D
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DOI：
10.1073/pnas.97.12.6751
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发表时间：
2000-06-06
影响因子：
11.1
通讯作者：
Conti，M
中科院分区：
文献类型：
--
作者：
Hansen，G;Jin，SLC;Conti，M
毒蕈碱胆碱能信号在控制正常气道功能和包括哮喘在内的肺部疾病的发展中起重要作用。在本文中，我们证明了缺乏camp特异性磷酸二酯酶（PDE4D）的小鼠气道不再对胆碱能刺激有反应。PDE4D - / -小鼠暴露于抗原后的气道高反应性也被消除，尽管肺部炎症浸润明显正常。胆碱能反应性的丧失是气道特有的，在心脏中没有观察到，并且与通过毒蕈碱受体的信号丧失有关，无法减少cAMP的积累。这些发现表明pde4dgene在cAMP稳态和气道胆碱能刺激以及过度反应性的发展中起重要作用。鉴于PDE4抑制剂的治疗潜力，我们的研究结果为针对单一PDE同工酶的新策略提供了基本原理。
Muscarinic cholinergic signaling plays an essential role in the control of the normal airway functions and in the development of pulmonary pathologies including asthma. In this paper we demonstrate that the airways of mice deficient in a cAMP-specific phosphodiesterase (PDE4D) are no longer responsive to cholinergic stimulation. Airway hyperreactivity that follows exposure to antigen was also abolished in PDE4D−/−mice, despite an apparently normal lung inflammatory infiltration. The loss of cholinergic responsiveness was specific to the airway, not observed in the heart, and was associated with a loss of signaling through muscarinic receptors with an inability to decrease cAMP accumulation. These findings demonstrate that thePDE4Dgene plays an essential role in cAMP homeostasis and cholinergic stimulation of the airway, and in the development of hyperreactivity. In view of the therapeutic potentials of PDE4 inhibitors, our findings provide the rationale for novel strategies that target a single PDE isoenzyme.