Jesper Säfholm1, Martijn L Manson2, Johan Bood2, Ingrid Delin2, Ann-Charlotte Orre3, Per Bergman4, Mamdoh Al-Ameri3, Sven-Erik Dahlén2, Mikael Adner2. 1. Unit for Experimental Asthma and Allergy Research, Institute of Environmental Medicine, and the Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden. Electronic address: jesper.safholm@ki.se. 2. Unit for Experimental Asthma and Allergy Research, Institute of Environmental Medicine, and the Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden. 3. Department of Cardiothoracic Surgery and Anesthesiology, Karolinska University Hospital, Stockholm, Sweden. 4. Department of Cardiothoracic Surgery and Anesthesiology, Karolinska University Hospital, Stockholm, Sweden; Department of Molecular Medicine and Surgery (MMK), Karolinska Institutet, Stockholm, Sweden.
Abstract
BACKGROUND: Inhaled prostaglandin (PG) E2 might inhibit asthmatic responses, but the mechanisms involved remain undefined. OBJECTIVE: We sought to characterize the direct and indirect effects of PGE2 on human small airways with particular reference to the receptors mediating the responses. METHODS: Contraction and relaxation were studied in isolated human bronchi with an inner diameter of 1 mm or less. RESULTS: Low concentrations of PGE2 (0.01-1 μmol/L) relaxed the bronchi precontracted by histamine. The bronchodilator response was inhibited by the E prostanoid (EP) subtype 4 receptor antagonist ONO-AE3-208 but unaffected by the EP2 receptor antagonist PF-04418948. Higher concentrations of PGE2 (10-100 μmol/L) contracted the small airways. However, the TP receptor agonists U-46,619, PGF2α, and PGD2 were more potent than PGE2. Moreover, the bronchoconstrictor responses to PGE2 and all other tested prostanoids, including the EP1/EP3 receptor agonist 17-phenyl trinor PGE2 and the partial FP receptor agonist AL-8810, were uniformly abolished by the TP receptor antagonist SQ-29,548. In the presence of TP and EP4 antagonists, PGE2 inhibited the mast cell-mediated bronchoconstriction resulting from anti-IgE challenge. Measurement of the release of histamine and cysteinyl leukotrienes documented that this bronchoprotective action of PGE2 was mediated by the EP2 receptor, unrelated to bronchodilation, and increased with time of exposure. CONCLUSION: The pharmacology of PGE2 in isolated human small airways was different from its profile in animal models. This first demonstration of powerful EP2 receptor-mediated inhibition of IgE-dependent contractions in human airways introduces a new selective target for the treatment of asthma. This EP2 control of mast cell-mediated bronchoconstriction is presumably exaggerated in patients with aspirin-exacerbated respiratory disease.
BACKGROUND: Inhaled prostaglandin (PG) E2 might inhibit asthmatic responses, but the mechanisms involved remain undefined. OBJECTIVE: We sought to characterize the direct and indirect effects of PGE2 on human small airways with particular reference to the receptors mediating the responses. METHODS: Contraction and relaxation were studied in isolated human bronchi with an inner diameter of 1 mm or less. RESULTS: Low concentrations of PGE2 (0.01-1 μmol/L) relaxed the bronchi precontracted by histamine. The bronchodilator response was inhibited by the E prostanoid (EP) subtype 4 receptor antagonist ONO-AE3-208 but unaffected by the EP2 receptor antagonist PF-04418948. Higher concentrations of PGE2 (10-100 μmol/L) contracted the small airways. However, the TP receptor agonists U-46,619, PGF2α, and PGD2 were more potent than PGE2. Moreover, the bronchoconstrictor responses to PGE2 and all other tested prostanoids, including the EP1/EP3 receptor agonist 17-phenyl trinor PGE2 and the partial FP receptor agonist AL-8810, were uniformly abolished by the TP receptor antagonist SQ-29,548. In the presence of TP and EP4 antagonists, PGE2 inhibited the mast cell-mediated bronchoconstriction resulting from anti-IgE challenge. Measurement of the release of histamine and cysteinyl leukotrienes documented that this bronchoprotective action of PGE2 was mediated by the EP2 receptor, unrelated to bronchodilation, and increased with time of exposure. CONCLUSION: The pharmacology of PGE2 in isolated human small airways was different from its profile in animal models. This first demonstration of powerful EP2 receptor-mediated inhibition of IgE-dependent contractions in human airways introduces a new selective target for the treatment of asthma. This EP2 control of mast cell-mediated bronchoconstriction is presumably exaggerated in patients with aspirin-exacerbated respiratory disease.
Authors: Berta Almoguera; Lyam Vazquez; Frank Mentch; John Connolly; Jennifer A Pacheco; Agnes S Sundaresan; Peggy L Peissig; James G Linneman; Catherine A McCarty; David Crosslin; David S Carrell; Todd Lingren; Bahram Namjou-Khales; John B Harley; Eric Larson; Gail P Jarvik; Murray Brilliant; Marc S Williams; Iftikhar J Kullo; Erik B Hysinger; Patrick M A Sleiman; Hakon Hakonarson Journal: Am J Respir Crit Care Med Date: 2017-02-15 Impact factor: 21.405