Mannitol triggers mast cell-dependent contractions of human small bronchi and prostacyclin bronchoprotection

Journal of Allergy and Clinical Immunolo.. - 8m ago Preview

 
 
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Publication date: Available online 14 June 2019

Source: Journal of Allergy and Clinical Immunology

Author(s): Jesper Säfholm, Martijn L. Manson, Johan Bood, Mamdoh Al-Ameri, Ann-Charlotte Orre, Johan Raud, Sven-Erik Dahlén, Mikael Adner

Abstract

Background

Clinical research supports that exercise-induced bronchoconstriction (EIB) is caused by hyperosmolar triggering of mast cells. The reaction can be mimicked by inhalation of mannitol, but it has paradoxically previously not been possible to replicate this mode of action of mannitol in isolated airways.

Objective

To establish an ex vivo model of EIB in human small bronchi.

Methods

Small bronchi (inner diameter 0.5-2 mm) from macroscopically healthy human lung tissue were obtained from 48 patients and mounted in organ baths. Contractions and mediator release was analysed after challenge with hyperosmolar mannitol (850mOsm).

Results

Ten minutes exposure to mannitol caused a small initial contraction (12±1% of maximum) that was followed by a second and much larger contraction (Emax:47±5%) when mannitol was washed-out. The mast cell stabilizer cromolyn reduced the second contraction (Emax:27±3%). Furthermore, this main contraction was abolished by the combination of antagonists of histamine and cysteinyl-leukotrienes (CysLTs) in the presence of indomethacin. Mannitol increased the release of the mast cell mediators histamine (9.0-fold), CysLTs (4.5-fold), and PGD2 (5.4-fold), as well as PGE2 (6.3-fold) and the prostacyclin metabolite 6-keto PGF1α (5.7-fold). In contrast, indomethacin alone enhanced the bronchoconstriction (Emax:68±6%). Likewise, receptor antagonists for EP2, EP4 or IP also enhanced the mannitol-induced bronchoconstriction (Emax: 67±5, 66±4 and 68±3%, respectively). In bronchi pre-contracted by carbachol, the IP agonist cicaprost induced profound relaxations.

Conclusion

This new protocol established an in vitro model for studies of EIB in isolated human bronchi. The IP receptor may be a new target for treatment of asthma.