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

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Science Signaling  24 Nov 2020:
Vol. 13, Issue 659, eaax0273
DOI: 10.1126/scisignal.aax0273

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Breathing better with osthole

β2-Adrenoreceptor agonists used to acutely relieve airway constriction in asthmatic patients become less effective with repeated use due to receptor desensitization and increase the risk of death. Using cells, lung slices, and mouse models of asthma, Wang et al. characterized osthole, a compound derived from a traditional Chinese medicine, in their search for compounds that induce bronchodilation through mechanisms other than activating β2-adrenoreceptors. Osthole promoted airway relaxation by inhibiting the phosphodiesterase PDE4D to prevent the breakdown of the second messenger cAMP, resulting in amplification of prostaglandin E2 signaling. These results suggest that variants of osthole could be developed to induce bronchodilation without desensitizing receptors or increasing the risk of death.

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.

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