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Thorax 67:19-25 doi:10.1136/thoraxjnl-2011-200365
  • Respiratory research
  • Original article

A role for sensory nerves in the late asthmatic response

  1. Maria G Belvisi1,2,5
  1. 1Respiratory Pharmacology Group, Pharmacology and Toxicology, National Heart and Lung Institute, Faculty of Medicine, London, UK
  2. 2Centre for Integrative Physiology and Pharmacology, Imperial College London, London, UK
  3. 3Department of Medicine, University of Vermont, Burlington, Vermont, USA
  4. 4Firestone Institute for Respiratory Health, St Joseph's Hospital and the Department of Medicine, McMaster University, Hamilton, Ontario, Canada
  5. 5Honorary Professor, Respiratory Research Group, University of Manchester, Manchester, UK
  1. Correspondence to Professor Maria G Belvisi, Imperial College London, Exhibition Road, London SW7 2AZ, UK; m.belvisi{at}imperial.ac.uk
  1. Contributors MGB and MAB conceived of the idea. MGB, MAB and KR designed the protocols. KR, MAB, JdA, MG and SAM performed the experiments. PMO'B, JRF and CGI gave critical advice on the experiments and the manuscript.

  • Received 18 April 2011
  • Accepted 5 July 2011
  • Published Online First 13 August 2011

Abstract

Background In allergic asthma, exposure to relevant antigens leads to an early asthmatic response (EAR) followed, in certain subjects, by a late asthmatic response (LAR). Although many subjects with asthma consider LAR to be one of the defining symptoms of their disease, and despite its widespread use in the clinical assessment of new therapeutic entities, the mechanism underlying the LAR remains unclear.

Method A study was undertaken using ovalbumin-sensitised and challenged Brown Norway rat and C57BL/6J mouse models which recapitulate phenotypic features of allergic asthma including the LAR and its susceptibility to clinically effective agents.

Results In conscious animals an EAR was followed by a LAR. The LAR was subjectively evidenced by audible (wheeze) and visual signs of respiratory distress associated with quantifiable changes in non-invasive lung function assessment. Treatments that attenuated the EAR failed to impact on the LAR and, while anaesthesia did not impact on EAR, it abolished LAR. A key role for airway sensory neuronal reflexes in the LAR was therefore hypothesised, which was confirmed by the blockade observed after administration of ruthenium red (non-selective cation channel blocker), HC-030031 (TRPA1 inhibitor) and tiotropium bromide (anticholinergic) but not JNJ-17203212 (TRPV1 inhibitor).

Conclusion These results suggest that LAR involves the following processes: allergen challenge triggering airway sensory nerves via the activation of TRPA1 channels which initiates a central reflex event leading to a parasympathetic cholinergic constrictor response. These data are supported by recent clinical trials suggesting that an anticholinergic agent improved symptoms and lung function in patients with asthma.

Footnotes

  • Funding The project was funded by the Medical Research Council (MRC), UK. MAB, SAM and MG were funded by project grants from the MRC (MAB, MG, G0800196; SAM, G0800195).

  • Competing interests None.

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

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