Prostaglandin D2 and the role of the DP1, DP2 and TP receptors in the control of airway reflex events

Prostaglandin D-2 (PGD(2)) causes cough and levels are increased in asthma suggesting that it may contribute to symptoms. Although the prostaglandin D-2 receptor 2 (DP2) is a target for numerous drug discovery programmes little is known about the actions of PGD2 on sensory nerves and cough. We used human and guinea pig bioassays, in vivo electrophysiology and a guinea pig conscious cough model to assess the effect of prostaglandin D-2 receptor (DP1), DP2 and thromboxane receptor antagonism on PGD(2) responses. PGD(2) caused cough in a conscious guinea pig model and an increase in calcium in airway jugular ganglia. Using pharmacology and receptor-deficient mice we showed that the DP1 receptor mediates sensory nerve activation in mouse, guinea pig and human vagal afferents. In vivo, PGD(2) and a DP1 receptor agonist, but not a DP2 receptor agonist, activated single airway C-fibres. Interestingly, activation of DP2 inhibited sensory nerve firing to capsaicin in vitro and in vivo. The DP1 receptor could be a therapeutic target for symptoms associated with asthma. Where endogenous PGD(2) levels are elevated, loss of DP2 receptor-mediated inhibition of sensory nerves may lead to an increase in vagally associated symptoms and the potential for such adverse effects should be investigated in clinical studies with DP2 antagonists.