Prostacyclin IP receptor activation blocks hyperosmolar-induced bronchoconstriction in isolated human small airways

Abstract

<b>Background:</b> Inhalation of mannitol increases airway osmolarity causing mast cell activation and airflow obstruction, mimicking exercise-induced bronchoconstriction (EIB). We have developed a human <i>in vitro</i> model of EIB using mannitol challenge. <b>Aim:</b> To test the hypothesis that prostacyclin (PGI₂) will inhibit hyperosmolar-induced constriction of human bronchi. This arose from our recent discovery that PGI₂ is released during EIB (Bood J. <i>et al.</i> JAP, 2015). <b>Methods:</b> Functional responses of human small bronchi (inner diameter 0.5-2 mm) were studied using lung tissue of patients undergoing lobectomy (n=25). <b>Results:</b> First, in carbachol pre-contracted bronchial segments, the PGI₂ analogue cicaprost induced a complete relaxation (pEC₅₀: 7.8 ± 0.1, n=8) which was antagonised by the IP receptor antagonist CAY 10441 (1 µM; pEC₅₀: 5.7 ± 0.6, n=8). Second, in preparations kept at baseline, a brief ten minute exposure to hyperosmolar (500 mM) mannitol was followed by a substantial contraction (E_max: 46.1 ± 3.2% of tissue maximal contraction, n=25). The contraction was abolished by antagonism of mast cell mediators by combination of antagonists of H₁-_, CysLT₁- and TP-receptors, as previously shown for the anti-IgE contractions (Säfholm J. <i>et al.</i> JACI 2015). Inhibition of the cyclooxygenase enzymes by indomethacin (3 µM) enhanced the bronchoconstriction (E_max: 67.6 ± 5.6%, n=16;p&lt;0.05). Moreover, pre-treatment with CAY 10441 (1 µM) enhanced the mannitol-induced bronchoconstriction to similar extent (E_max: 66.4 ± 3.5, n=7;p&lt;0.05). <b>Conclusions:</b> Prostacyclin has potential as bronchoprotective agent presumably by virtue of being a previously unrecognized potent dilator of human airways.