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Bronchial Thermoplasty: A Novel Therapeutic Approach to Severe Asthma
Published on: November 4, 2010
EP4 receptor as a new target for bronchodilator therapy
James Buckley1, Mark A Birrell, Sarah A Maher
1Respiratory Pharmacology, Pharmacology and Toxicology Section, Imperial College London, Faculty of Medicine, National Heart and Lung Institute, Sir Alexander Fleming Building, London SW7 2AZ, UK.
Thorax
|May 25, 2011
Summary
Prostaglandin E(2) (PGE(2)) relaxes airways via EP(2) and EP(4) receptors. This study identified EP(4) receptors in human airways, explaining why EP(2) agonists failed in clinical trials for asthma and COPD.
Area of Science:
- Pharmacology
- Respiratory Medicine
- Molecular Biology
Background:
- Asthma and COPD are inflammatory airway diseases with limited treatment options.
- Current bronchodilators have limitations in efficacy and safety for severe disease.
- Prostaglandin E(2) (PGE(2)) is a molecule with potential bronchodilatory effects.
Purpose of the Study:
- To identify the specific receptors mediating PGE(2)-induced airway relaxation.
- To investigate these receptors across multiple species, including humans.
- To understand the basis for clinical trial failures of EP(2) receptor agonists.
Main Methods:
- Utilized a wide array of pharmacological tools and selective agonists/antagonists.
- Examined isolated airway tissues from guinea pigs, mice, rats, monkeys, and humans.
- Employed EP(2) receptor-deficient mice (Ptger2) for genetic validation.
Main Results:
- Confirmed EP(2) receptor mediation of PGE(2) relaxation in guinea pig, mouse, and monkey trachea.
- Identified EP(4) receptor mediation of PGE(2) relaxation in rat trachea.
- Demonstrated a significant role for EP(4) receptors in human airway relaxation in vitro, contrasting with prior studies.
- Observed relaxant activity of an EP(2) agonist (AH13205) in guinea pig but not human airways.
Conclusions:
- The EP(4) receptor is a key mediator of PGE(2)-induced relaxation in human airways.
- These findings provide a mechanistic explanation for the lack of efficacy of selective EP(2) receptor agonists in clinical studies.
- Targeting the EP(4) receptor represents a potential novel therapeutic strategy for bronchodilator development in asthma and COPD.
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