EP4 agonists have reduced bronchodilation activity in patients with Group III pulmonary hypertension

[Speaker] Xavier Norel:1
[Co-author] Chabha Benyahia:1, Gulsev Ozen:2, Herve Mal:4, Adam M. Silverstein:3, Richard Bayles:1, Andrew C. Nelsen:3, Yves Castier:4, Lucie H. Clapp:5, Dan Longrois:1,4
1:INSERM, UMR-S 1148, CHU X. Bichat, Paris, France; - Paris 13 University, USPC, 93430 Villetaneuse, France, 2:Faculty of Pharmacy, Department of Pharmacology, Istanbul University, Istanbul 34116, Turkey, 3:United Therapeutics, Research Triangle Park, NC 27709, USA, 4:Hopital Bichat-Claude Bernard, AP-HP, Paris Diderot University, USPC, 75018 Paris, France, 5:Department of Medicine, University College London, London WC1E 6JF, UK

Introduction: Pulmonary hypertension (PH)-group III is secondary to chronic lung diseases, including chronic obstructive pulmonary disease, lung fibrosis or emphysema (1). In these patients, the beneficial clinical effects of prostaglandin (PG)I2 mimetics are illustrated by decreased pulmonary arterial pressure, reduced dyspnea and improved capacity to perform physical efforts. These effects could be modulated by changes in bronchomotricity, mostly when delivered as inhaled drugs. Previously, it has been shown that PGE2/PGI2 mimetics induce potent relaxations of human bronchi from control patients via EP4 or IP receptors (2-3). However, the effects of PGE2/PGI2 mimetics on the human bronchial reactivity in specimens from PH patients and the activated receptors are unknown. That was the aim of this study.
Methods: The muscular tone of bronchial preparations derived from control and PH-group 3 patients was measured with an organ bath system. The different preparations were stimulated by PGE2/PGI2 mimetics and pharmacological studies were performed with different antagonists. The expression of EP4, EP2, IP and DP receptors were analyzed by Western blot and real-time PCR in both types of preparations.
Results: The relaxations induced by different EP4 agonists, PGE2, L-902688, ONO-AE1-329 and the (IP, EP4) agonist iloprost, were significantly decreased in human bronchi from PH patients as compared to controls. However, the relaxations produced by treprostinil, beraprost, MRE-269 (IP agonists) and ONO-AE1-259 (EP2 agonist) were not different between these tissues. The EP4 and IP receptor densities and mRNA expression were significantly lower (50-70%) in human bronchi from PH patients.
Conclusions: This study shows that PGI2 mimetics induce strong bronchodilation in control and PH-Group III patient samples, whereas PGE2 and EP4 agonists have significantly reduced bronchodilation in PH-Group III patient samples compared to control samples. From these results, the most potent therapies to activate IP receptor and those targeting the prevention/reversal of EP4 down regulation may be the most effective for restoring the respiratory function in these patients.
References: (1) Galie et al, 2016, PMID: 26320113 ; (2) Benyahia et al, 2012, PMID: 22244823 ; (3) Norel et al. 1999, PMID: 10193766.
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