Airway relaxation mechanisms and structural basis of osthole for improving lung function in asthma

Sheng Wang, Yan Xie, Yan Wu Huo, Yan Li, Peter W. Abel, Haihong Jiang, Xiaohan Zou, Hai Zhan Jiao, Xiaolin Kuang, Dennis W. Wolff, You Guo Huang, Thomas B. Casale, Reynold A. Panettieri, Taotao Wei, Zhengyu Cao, Yaping Tu

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article numbereaax0273
JournalScience signaling
Volume13
Issue number659
DOIs
StatePublished - Nov 24 2020

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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