PT  - JOURNAL ARTICLE
AU  - Säfholm, Jesper
AU  - Bood, Johan
AU  - Dahlén, Sven-Erik
AU  - Adner, Mikael
TI  - Prostacyclin IP receptor activation blocks hyperosmolar-induced bronchoconstriction in isolated human small airways
AID  - 10.1183/13993003.congress-2016.PA5054
DP  - 2016 Sep 01
TA  - European Respiratory Journal
PG  - PA5054
VI  - 48
IP  - suppl 60
4099  - http://erj.ersjournals.com/content/48/suppl_60/PA5054.short
4100  - http://erj.ersjournals.com/content/48/suppl_60/PA5054.full
SO  - Eur Respir J2016 Sep 01; 48
AB  - Background: Inhalation of mannitol increases airway osmolarity causing mast cell activation and airflow obstruction, mimicking exercise-induced bronchoconstriction (EIB). We have developed a human in vitro model of EIB using mannitol challenge.Aim: 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. et al. JAP, 2015).Methods: Functional responses of human small bronchi (inner diameter 0.5-2 mm) were studied using lung tissue of patients undergoing lobectomy (n=25).Results: 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 (Emax: 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. et al. JACI 2015). Inhibition of the cyclooxygenase enzymes by indomethacin (3 µM) enhanced the bronchoconstriction (Emax: 67.6 ± 5.6%, n=16;p<0.05). Moreover, pre-treatment with CAY 10441 (1 µM) enhanced the mannitol-induced bronchoconstriction to similar extent (Emax: 66.4 ± 3.5, n=7;p<0.05).Conclusions: Prostacyclin has potential as bronchoprotective agent presumably by virtue of being a previously unrecognized potent dilator of human airways.