Respiratory Pharmacology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, UK.
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.
Eur Respir J. 2015 Apr;45(4):1108-18. doi: 10.1183/09031936.00061614. Epub 2014 Oct 16.
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.
前列腺素 D2（PGD2）可引起咳嗽，且在哮喘中水平升高，提示其可能与症状有关。尽管前列腺素 D2 受体 2（DP2）是许多药物发现计划的靶标，但对于 PGD2 对感觉神经和咳嗽的作用知之甚少。我们使用人体和豚鼠生物测定、体内电生理学和豚鼠清醒咳嗽模型来评估前列腺素 D2 受体（DP1）、DP2 和血栓素受体拮抗剂对 PGD2 反应的影响。PGD2 在清醒豚鼠模型中引起咳嗽，并增加气道颈静脉神经节中的钙。使用药理学和受体缺陷小鼠，我们表明 DP1 受体介导小鼠、豚鼠和人迷走传入神经的感觉神经激活。在体内，PGD2 和 DP1 受体激动剂，但不是 DP2 受体激动剂，激活了单个气道 C 纤维。有趣的是，DP2 受体的激活抑制了体外和体内辣椒素引起的感觉神经放电。DP1 受体可能是与哮喘相关症状的治疗靶点。在内源性 PGD2 水平升高的情况下，DP2 受体介导的感觉神经抑制丧失可能导致与迷走神经相关的症状增加，应在 DP2 拮抗剂的临床研究中调查此类不良反应的可能性。
