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

被引:12
作者
Safholm, Jesper [1 ,2 ]
Manson, Martijn L. [1 ,2 ]
Bood, Johan [1 ,2 ]
Al-Ameri, Mamdoh [3 ,4 ]
Orre, Ann-Charlotte [4 ]
Raud, Johan [1 ,2 ]
Dahlen, Sven-Erik [1 ,2 ]
Adner, Mikael [1 ,2 ]
机构
[1] Karolinska Inst, Inst Environm Med, Biomedicum 5B,Solnavagen 9, SE-17165 Solna, Sweden
[2] Karolinska Inst, Ctr Allergy Res, Solna, Sweden
[3] Karolinska Inst, Dept Mol Med & Surg MMK, Solna, Sweden
[4] Karolinska Univ Hosp, Dept Cardiothorac Surg & Anesthesiol, Solna, Sweden
基金
瑞典研究理事会;
关键词
Hyperosmolar challenge; exercise-induced bronchoconstriction; prostaglandin D-2; prostaglandin E-2; prostaglandin I-2; EP2; receptor; EP4; prostacyclin receptor; histamine; nonsteroidal anti-inflammatory drugs; EXERCISE-INDUCED BRONCHOCONSTRICTION; SODIUM CROMOGLYCATE; ASTHMATIC SUBJECTS; SMOOTH-MUSCLE; RELEASE; RECEPTOR; REFRACTORINESS; LEUKOTRIENES; HYPERPNEA; INDOMETHACIN;
D O I
10.1016/j.jaci.2019.04.031
中图分类号
R392 [医学免疫学];
学科分类号
100102 ;
摘要
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(1 alpha) (5.7-fold). In contrast, indomethacin alone enhanced the bronchoconstriction (E-max, 68% +/- 6%). Likewise, receptor antagonists for PGE(2) (EP2 and EP4) 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.
引用
收藏
页码:984 / 992
页数:9
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