Prostaglandin E2 Mediates Cough via the EP3 Receptor Implications for Future Disease Therapy

Rationale: A significant population of patients with severe asthma and chronic obstructive pulmonary disease is less responsive to beta(2)-adrenoceptor agonists and corticosteroids, and there are possible safety issues concerning long-term use of these drugs. Inhaled prostaglandin E-2 (PGE(2)) is antiinflammatory and a bronchodilator in patients with asthma, but it also causes cough. Objectives: We aimed to identify the receptor involved in PGE(2)-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 PGE(2)-induced depolarization of sensory nerves in human, mouse, and guinea pig. Further supporting evidence comes from data showing that responses to PGE(2) 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 PGE(2)-induced cough. Conclusions: Identification of the receptor mediating PGE2-induced cough represents a key step in developing a drug that is anti-inflammatory and a bronchodilator but without unwanted side effects.