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Airway biology
Original article
EP4 receptor as a new target for bronchodilator therapy
  1. James Buckley1,
  2. Mark A Birrell1,
  3. Sarah A Maher1,
  4. Anthony T Nials2,
  5. Deborah L Clarke1,
  6. Maria G Belvisi1
  1. 1Respiratory Pharmacology, Pharmacology and Toxicology Section, Imperial College London, Faculty of Medicine, National Heart and Lung Institute, London, UK
  2. 2Respiratory CEDD, GlaxoSmithKline Research and Development, Medicines Research Centre, Stevenage, Hertfordshire, UK
  1. Correspondence to Professor Maria G Belvisi, Respiratory Pharmacology, Pharmacology and Toxicology Section, Imperial College London, Faculty of Medicine, National Heart and Lung Institute, Sir Alexander Fleming Building, London SW7 2AZ, UK; m.belvisi{at}imperial.ac.uk

Abstract

Background Asthma and chronic obstructive pulmonary disease are airway inflammatory diseases characterised by airflow obstruction. Currently approved bronchodilators such as long-acting β2 adrenoceptor agonists are the mainstay treatments but often fail to relieve symptoms of chronic obstructive pulmonary disease and severe asthma and safety concerns have been raised over long-term use. The aim of the study was to identify the receptor involved in prostaglandin E2 (PGE2)-induced relaxation in guinea pig, murine, monkey, rat and human airways in vitro.

Methods Using an extensive range of pharmacological tools, the relaxant potential of PGE2 and selective agonists for the EP1–4 receptors in the presence and absence of selective antagonists in guinea pig, murine, monkey, rat and human isolated airways was investigated.

Results In agreement with previous studies, it was found that the EP2 receptor mediates PGE2-induced relaxation of guinea pig, murine and monkey trachea and that the EP4 receptor mediates PGE2-induced relaxation of the rat trachea. These data have been confirmed in murine airways from EP2 receptor-deficient mice (Ptger2). In contrast to previous publications, a role for the EP4 receptor in relaxant responses in human airways in vitro was found. Relaxant activity of AH13205 (EP2 agonist) was also demonstrated in guinea pig but not human airway tissue, which may explain its failure in clinical studies.

Conclusion Identification of the receptor mediating PGE2-induced relaxation represents a key step in developing a novel bronchodilator therapy. These data explain the lack of bronchodilator activity observed with selective EP2 receptor agonists in clinical studies.

  • Relaxation
  • airway smooth muscle
  • prostanoids
  • prostanoid receptors
  • asthma pharmacology
  • respiratory muscles
  • asthma pharmacology
  • respiratory muscles

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.

https://doi.org/10.1136/thx.2010.158568

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    Footnotes

    • Funding The research project and SAM were funded by a project grant from the Medical Research Council (MRC) UK (G0800195). MAB was funded by a grant from the MRC (G0800196). DLC was funded by an MRC project grant Experimental Medicine Grant (G0502019). The human tissue experiments in this study were undertaken with the support of the NIHR Biomedical Research Unit in Advanced Lung Disease at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London and partly funded by the NIHR Biomedical Research Unit funding scheme. JB was funded by a Studentship from a Capacity Building Award in Integrative Mammalian Biology funded by BBSRC, BPS, HEFCE KTN and MRC.

    • Competing interests None.

    • Patient consent Obtained.

    • Ethics approval This study was conducted with the approval of the Royal Brompton and Harefield ethics committee.

    • Provenance and peer review Not commissioned; externally peer reviewed.