title: Prostaglandin D2 and the role of the DP1, DP2 and TP receptors in the control of airway reflex events.
abstract: Prostaglandin D2 (PGD2) causes cough and levels are increased in asthma suggesting that it may contribute to symptoms. Although the prostaglandin D2 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 D2 receptor (DP1), DP2 and thromboxane receptor antagonism on PGD2 responses. PGD2 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, PGD2 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 PGD2 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.
authors.affiliation: Respiratory Pharmacology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, UK.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Maher
authors.affiliation: Respiratory Pharmacology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, UK MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, London, UK.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Birrell
authors.affiliation: Respiratory Pharmacology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, UK.
authors.forename: John J
authors.initials: JJ
authors.lastname: Adcock
authors.affiliation: Respiratory Pharmacology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, UK.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Wortley
authors.affiliation: Respiratory Pharmacology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, UK.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Dubuis
authors.affiliation: Respiratory Pharmacology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, UK.
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Bonvini
authors.affiliation: Respiratory Pharmacology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, UK.
authors.forename: Megan S
authors.initials: MS
authors.lastname: Grace
authors.affiliation: Respiratory Pharmacology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, UK MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, London, UK m.belvisi@imperial.ac.uk.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Belvisi
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000188:drug therapy / Q000378:metabolism; D001986:Bronchial Spasm / Q000378:metabolism / Q000503:physiopathology*; D002211:Capsaicin / Q000494:pharmacology; D002478:Cells, Cultured; D003371:Cough / Q000378:metabolism / Q000503:physiopathology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D006168:Guinea Pigs; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015230:Prostaglandin D2 / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000378:metabolism; D017482:Receptors, Thromboxane / Q000378:metabolism*; D012680:Sensitivity and Specificity; D046509:Tissue Culture Techniques; D050680:Transcription Factor DP1 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014630:Vagus Nerve / Q000187:drug effects*
chemical_list: D004268:DNA-Binding Proteins; D007211:Indoles; C518174:MK-0524; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; C094103:TFDP2 protein, human; D050680:Transcription Factor DP1; D014157:Transcription Factors; D015230:Prostaglandin D2; D002211:Capsaicin; C036293:prostaglandin D2 receptor