prostaglandin-d2 and Cough

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.

Topics: Administration, Inhalation; Animals; Bronchial Hyperreactivity; Bronchial Spasm; Capsaicin; Cells, Cultured; Cough; Disease Models, Animal; DNA-Binding Proteins; Guinea Pigs; Humans; Indoles; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin; Receptors, Thromboxane; Sensitivity and Specificity; Tissue Culture Techniques; Transcription Factor DP1; Transcription Factors; Vagus Nerve

The aim of this study was to explore the pathogenesis of chronic cough caused by non-acid reflux.. Seven patients with chronic cough due to non-acid reflux, 12 patients with chronic cough due to acid reflux, 10 patients with gastro-oesophageal reflux disease without cough and 12 healthy volunteers were recruited for the study. All subjects underwent oesophageal multi-channel intraluminal impedance measurements combined with pH monitoring, and assessment of cough reflex sensitivity to capsaicin and induced sputum cytology. The concentrations of substance P, mast cell tryptase, prostaglandin D2 and histamine in induced sputum were measured by ELISA.. Cough threshold C2 and C5 did not differ between patients with chronic cough due to non-acid or acid reflux, but the values were significantly lower than those for patients with gastro-oesophageal reflux disease without cough and healthy volunteers. Weakly acidic reflux episodes were obviously more frequent in patients with chronic cough due to non-acid reflux than in the other three groups. Sputum substance P and mast cell tryptase concentrations were remarkably increased in patients with chronic cough, but were similar for those with cough due to non-acid or acid reflux. There were significant inverse correlations between substance P levels and cough threshold C2 or C5 in patients with cough due to non-acid or acid reflux, and between mast cell tryptase levels and cough threshold C2 in patients with cough due to acid reflux.. Chronic cough due to non-acid reflux may be related to cough reflex hypersensitivity caused by neurogenic airway inflammation and mast cell activation, in which weakly acidic reflux is possibly a major factor.

Topics: Adult; Aged; Asthma; Capsaicin; Chronic Disease; Cough; Cross-Sectional Studies; Female; Gastroesophageal Reflux; Histamine; Humans; Male; Middle Aged; Prospective Studies; Prostaglandin D2; Reflex; Respiratory Function Tests; Sputum; Substance P; Tryptases

Prostaglandin D2 (PGD2) and some naturally occurring and synthetic prostaglandin (PG) analogues were evaluated for irritant/ tussive activity in cats. PGD2, PGF2 alpha and ICI81008 were potent tussive agents when inhaled, producing both an early and late phase of coughing. In addition all three prostaglandins decreased respiratory rate. In contrast PGE2, PGE1 and PGA1 were 100-1000 times less potent than PGF2 alpha as irritants and weakly stimulated respiratory rate. The PGE class of compounds only produced an early phase of coughing. The rank order of early phase tussive activity was ICI81008 greater than PGF2 alpha greater than PGF2 beta much greater than PGE1 = PGE2 = PGA1. This rank order is similar to that characterising the prostanoid 'X' contractant or class II receptor(s).

Topics: Aerosols; Animals; Cats; Cough; Dinoprost; Prostaglandin D2; Prostaglandins D; Prostaglandins F; Prostaglandins F, Synthetic; Receptors, Cell Surface; Receptors, Prostaglandin; Respiration