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Prostaglandin E₂ Mediates Cough via the EP₃ Receptor

Implications for Future Disease Therapy

¹ Respiratory Pharmacology, Airways Diseases, Imperial College London, Faculty of Medicine, National Heart and Lung Institute, London, United Kingdom

Correspondence and requests for reprints should be addressed to Maria G. Belvisi, Ph.D., Respiratory Pharmacology, Airways Diseases, Imperial College London, Faculty of Medicine, National Heart and Lung Institute, Sir Alexander Fleming Building, London, SW7 2AZ, UK. E-mail: m.belvisi{at}imperial.ac.uk

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.

Key Words: airway sensory nerves • vagus nerve • cough • prostanoids • prostanoid receptors

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Prostaglandin E2 (PGE2) has been shown to be antiinflammatory and a bronchodilator in animal models and subjects with asthma. However PGE2 causes cough as a side effect and the receptor mediating this effect is currently unknown. What This Study Adds to the Field We have identified the receptor involved in PGE2-induced cough, which could lead to the development of a novel therapy for airway disease that is both a bronchodilator and antiinflammatory but devoid of tussive side effects.