RT Journal Article
SR Electronic
T1 A role for sensory nerves in the late asthmatic response
JF Thorax
JO Thorax
FD BMJ Publishing Group Ltd and British Thoracic Society
SP 19
OP 25
DO 10.1136/thoraxjnl-2011-200365
VO 67
IS 1
A1 Kristof Raemdonck
A1 Jorge de Alba
A1 Mark A Birrell
A1 Megan Grace
A1 Sarah A Maher
A1 Charles G Irvin
A1 John R Fozard
A1 Paul M O'Byrne
A1 Maria G Belvisi
YR 2012
UL http://thorax.bmj.com/content/67/1/19.abstract
AB 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.