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

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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 We sought 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 were analyzed after challenge with hyperosmolar mannitol (850 mOsm). Results Ten minutes of exposure to mannitol caused a small initial contraction (12% ± 1% of maximum) that was followed by a second and much larger contraction (maximum effect [E max ], 47% ± 5%) when mannitol was washed out. The mast cell stabilizer cromolyn reduced the second contraction (E max , 27% ± 3%). Furthermore, this main contraction was abolished by the combination of antagonists of histamine and cysteinyl leukotrienes in the presence of indomethacin. Mannitol increased the release of the mast cell mediators histamine (9.0-fold), cysteinyl leukotrienes (4.5-fold), and prostaglandin (PG) D 2 (5.4-fold), as well as PGE 2 (6.3-fold) and the prostacyclin metabolite 6-keto PGF 1α (5.7-fold). In contrast, indomethacin alone enhanced the bronchoconstriction (E max , 68% ± 6%). Likewise, receptor antagonists for PGE 2 (EP 2 and EP 4 ) and prostacyclin (IP) also enhanced the mannitol-induced bronchoconstriction (E max , 67% ± 5%, 66% ± 4%, and 68% ± 3%, respectively). In bronchi precontracted by carbachol, the IP receptor agonist cicaprost induced profound relaxation. Conclusion This new protocol established an in vitro model for studies of EIB in isolated human bronchi. The IP receptor might be a new target for asthma treatment.

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