2. Academic Validation
  3. Airway relaxation mechanisms and structural basis of osthole for improving lung function in asthma

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

  • Sci Signal. 2020 Nov 24;13(659):eaax0273. 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 Jr 7,  Taotao Wei 8,  Zhengyu Cao 9,  Yaping Tu 10
Affiliations

Affiliations

  • 1 National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
  • 2 Department of Pharmacology and Neuroscience, Creighton University School of Medicine, Omaha, NE 68178, USA.
  • 3 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 4 State Key Laboratory of Natural Medicines and Jiangsu Provincial Key Laboratory for TCM Evaluation and Translational Development, China Pharmaceutical University, Nanjing 211198, China.
  • 5 Kansas City University of Medicine and Biosciences-Joplin, Joplin, MO 64804, USA.
  • 6 Department of Internal Medicine, University of South Florida School of Medicine, Tampa, FL 33612, USA.
  • 7 Rutgers Institute for Translational Medicine and Science, Rutgers Biomedical and Health Sciences, Rutgers University, New Brunswick, NJ 08901, USA.
  • 8 National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. [email protected] [email protected] [email protected].
  • 9 State Key Laboratory of Natural Medicines and Jiangsu Provincial Key Laboratory for TCM Evaluation and Translational Development, China Pharmaceutical University, Nanjing 211198, China. [email protected] [email protected] [email protected].
  • 10 Department of Pharmacology and Neuroscience, Creighton University School of Medicine, Omaha, NE 68178, USA. [email protected] [email protected] [email protected].
PMID: 33234690 DOI: 10.1126/scisignal.aax0273
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.

Figures
Products