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Airway relaxation mechanisms and structural basis of osthole for improving lung function in asthma
Science Signaling ( IF 6.7 ) Pub Date : 2020-11-24 , DOI: 10.1126/scisignal.aax0273
Sheng Wang 1, 2, 3 , Yan Xie 2 , Yan-Wu Huo 1 , Yan Li 4 , Peter W Abel 2 , Haihong Jiang 2 , Xiaohan Zou 4 , Hai-Zhan Jiao 1, 3 , Xiaolin Kuang 1, 3 , Dennis W Wolff 5 , You-Guo Huang 1 , Thomas B Casale 6 , Reynold A Panettieri 7 , Taotao Wei 1 , Zhengyu Cao 4 , Yaping Tu 2
Affiliation  

Overuse of β2-adrenoceptor agonist bronchodilators evokes receptor desensitization, decreased efficacy, and an increased risk of death in asthma patients. Bronchodilators that do not target β2-adrenoceptors represent a critical unmet need for asthma management. Here, we characterize the utility of osthole, a coumarin derived from a traditional Chinese medicine, in preclinical models of asthma. In mouse precision-cut lung slices, osthole relaxed preconstricted airways, irrespective of β2-adrenoceptor desensitization. Osthole administered in murine asthma models attenuated airway hyperresponsiveness, a hallmark of asthma. Osthole inhibited phosphodiesterase 4D (PDE4D) activity to amplify autocrine prostaglandin E2 signaling in airway smooth muscle cells that eventually triggered cAMP/PKA-dependent relaxation of airways. The crystal structure of the PDE4D complexed with osthole revealed that osthole bound to the catalytic site to prevent cAMP binding and hydrolysis. Together, our studies elucidate a specific molecular target and mechanism by which osthole induces airway relaxation. Identification of osthole binding sites on PDE4D will guide further development of bronchodilators that are not subject to tachyphylaxis and would thus avoid β2-adrenoceptor agonist resistance.



中文翻译:

蛇床子素改善哮喘肺功能的气道舒张机制及结构基础

过度使用 β2-肾上腺素受体激动剂支气管扩张剂会引起哮喘患者的受体脱敏、疗效降低和死亡风险增加。不针对 β2-肾上腺素能受体的支气管扩张剂代表了哮喘管理的关键未满足需求。在这里,我们描述了从传统中药中提取的香豆素,在哮喘的临床前模型中的效用。在小鼠精确切割的肺切片中,蛇床子素可以放松预收缩的气道,而与 β2-肾上腺素能受体脱敏无关。在小鼠哮喘模型中施用 Osthole 可减弱气道高反应性,这是哮喘的标志。Osthole 抑制磷酸二酯酶 4D (PDE4D) 活性以放大自分泌前列腺素 E 2气道平滑肌细胞中的信号传导,最终触发气道的 cAMP/PKA 依赖性松弛。与蛇床子素复合的 PDE4D 的晶体结构表明,蛇床子素与催化位点结合以防止 cAMP 结合和水解。总之,我们的研究阐明了蛇床子素诱导气道松弛的特定分子靶标和机制。PDE4D 上蛇床子素结合位点的鉴定将指导支气管扩张剂的进一步开发,这些支气管扩张剂不受快速免疫反应的影响,从而避免 β2-肾上腺素受体激动剂的耐药性。

更新日期:2020-11-25
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