You are here

Article Text

Article menu
Original articles
Cough
Transient receptor potential channels mediate the tussive response to prostaglandin E2 and bradykinin
  1. Megan Grace1,2,
  2. Mark A Birrell1,2,
  3. Eric Dubuis1,
  4. Sarah A Maher1,2,
  5. Maria G Belvisi1,2,3
  1. 1Respiratory Pharmacology Group, Pharmacology and Toxicology Section, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, UK
  2. 2Centre for Integrative Physiology and Pharmacology, Imperial College London, London, UK
  3. 3Respiratory Research Group, University of Manchester, Wythenshawe Hospital, Manchester, UK
  1. Correspondence to Professor Mara Belvisi, Imperial College London, Exhibition Road, London SW7 2AZ, UK; m.belvisi{at}imperial.ac.uk

Abstract

Background Cough is the most frequent reason for consultation with a family doctor, or with a general or respiratory physician. Treatment options are limited and a recent meta-analysis concluded that over-the-counter remedies are ineffective and there is increasing concern about their use in children. Endogenous inflammatory mediators such as prostaglandin E2 (PGE2) and bradykinin (BK), which are often elevated in respiratory disease states, are also known to cause cough by stimulating airway sensory nerves. However, how this occurs is not understood.

Methods We hypothesised that the transient receptor potential (TRP) channels, TRPA1 and TRPV1, may have a role as ‘common effectors’ of tussive responses to these agents. We have employed a range of in vitro imaging and isolated tissue assays in human, murine and guinea pig tissue and an in vivo cough model to support this hypothesis.

Results Using calcium imaging we demonstrated that PGE2 and BK activated isolated guinea pig sensory ganglia and evoked depolarisation (activation) of vagal sensory nerves, which was inhibited by TRPA1 and TRPV1 blockers (JNJ17203212 and HC-030031). These data were confirmed in vagal sensory nerves from TRPA1 and TRPV1 gene deleted mice. TRPV1 and TRPA1 blockers partially inhibited the tussive response to PGE2 and BK with a complete inhibition obtained in the presence of both antagonists together in a guinea pig conscious cough model.

Conclusion This study identifies TRPA1 and TRPV1 channels as key regulators of tussive responses elicited by endogenous and exogenous agents, making them the most promising targets currently identified in the development of anti-tussive drugs.

  • Cough
  • sensory nerves
  • transient receptor potential channels
  • lung
  • prostanoids
  • asthma
  • COPD mechanisms
  • COPD exacerbations
  • COPD pathology
  • COPD pharmacology
  • cough/mechanisms/pharmacology
  • respiratory infection
  • viral infection
  • asthma mechanisms
  • asthma pharmacology
  • emphysema
  • primary pulmonary hypertension

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/thoraxjnl-2011-201443

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    View Full Text

    Supplementary materials

    • Supplementary Data

      This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

      Files in this Data Supplement:

    Footnotes

    • Additional materials are published online only. To view these files please visit the journal online (http://dx.doi.org/10.1136/thoraxjnl-2011-201443).

    • Funding MAB, SAM and MG were funded by project grants from the Medical Research Council (MRC, UK) (MAB, G0800196; SAM, MG, G0800195). The human tissue experiments in this study were undertaken with the support of the NIHR Respiratory Disease Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London. ED was funded by a Wellcome Trust project grant (089301/Z/09/Z).

    • Competing interests None.

    • Ethics approval Ethics approval was provided by Royal Brompton & Harefield Trust.

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