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Most airway diseases, including chronic obstructive pulmonary disease (COPD), are associated with excessive coughing. The extent to which this may be a consequence of increased activation of vagal afferents by pathology in the airways (e.g., inflammatory mediators, excessive mucus) or an altered neuronal phenotype is unknown. Understanding whether respiratory diseases are associated with dysfunction of airway sensory nerves has the potential to identify novel therapeutic targets.To assess the changes in cough responses to a range of inhaled irritants in COPD and model these in animals to investigate the underlying mechanisms.Cough responses to inhaled stimuli in patients with COPD, healthy smokers, refractory chronic cough, asthma, and healthy volunteers were assessed and compared with vagus/airway nerve and cough responses in a cigarette smoke (CS) exposure guinea pig model.Patients with COPD had heightened cough responses to capsaicin but reduced responses to prostaglandin E2 compared with healthy volunteers. Furthermore, the different patient groups all exhibited different patterns of modulation of cough responses. Consistent with these findings, capsaicin caused a greater number of coughs in CS-exposed guinea pigs than in control animals; similar increased responses were observed in ex vivo vagus nerve and neuron cell bodies in the vagal ganglia. However, responses to prostaglandin E2 were decreased by CS exposure.CS exposure is capable of inducing responses consistent with phenotypic switching in airway sensory nerves comparable with the cough responses observed in patients with COPD. Moreover, the differing profiles of cough responses support the concept of disease-specific neurophenotypes in airway disease. Clinical trial registered with www.clinicaltrials.gov (NCT 01297790).

Due to recent safety concerns with beta 2 adrenoceptor agonists (e.g. salbutamol), there has been an ongoing attempt to identify novel bronchodilator agents for use in asthma and COPD. Due to its beneficial action on airway calibre, prostaglandin E2 (PGE2) was previously investigated as a potential therapy, however in addition to bronchodilator activity, in clinical studies PGE2 also produced tussive effects and bronchial irritancy. As PGE2 mediates its actions via a number of different prostanoid receptors, it was hoped that by selectively targeting individual receptors, the beneficial actions could be selected. In a previous study (Nials et al 1993), the EP2 receptor was identified as mediating PGE2-induced relaxation however when tested clinically, an EP2 agonist (AH13205) produced disappointing results.

Rationale: A significant population of patients with severe asthma and chronic obstructive pulmonary disease is less responsive to β2-adrenoceptor agonists and corticosteroids, and there are possible safety issues concerning long-term use of these drugs. Inhaled prostaglandin E2 (PGE2) is antiinflammatory and a bronchodilator in patients with asthma, but it also causes cough. Objectives: We aimed to identify the receptor involved in PGE2-induced sensory nerve activation and cough using a range of in vitro and in vivo techniques. Methods: Depolarization of vagal sensory nerves (human, mouse, and guinea pig) was assessed as an indicator of sensory nerve acitivity. Cough was measured in a conscious guinea pig model. Measurements and Main Results: Using an extensive range of pharmacological tools, we identified that the EP3 receptor mediates PGE2-induced depolarization of sensory nerves in human, mouse, and guinea pig. Further supporting evidence comes from data showing that responses to PGE2 are virtually abolished in isolated vagus nerves from EP3-deficient mice (Ptger3−/−). Finally, we demonstrated the role of the EP3 receptor in vivo using a selective EP3 antagonist to attenuate PGE2-induced cough. Conclusions: Identification of the receptor mediating PGE2-induced cough represents a key step in developing a drug that is antiinflammatory and a bronchodilator but without unwanted side effects.