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.
journal_name
Sci Signaljournal_title
Science signalingauthors
Wang S,Xie Y,Huo YW,Li Y,Abel PW,Jiang H,Zou X,Jiao HZ,Kuang X,Wolff DW,Huang YG,Casale TB,Panettieri RA Jr,Wei T,Cao Z,Tu Ydoi
10.1126/scisignal.aax0273subject
Has Abstractpub_date
2020-11-24 00:00:00issue
659eissn
1945-0877issn
1937-9145pii
13/659/eaax0273journal_volume
13pub_type
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