Evidence of mast cell activation and leukotriene release after mannitol inhalation

Abstract

The aim of this study was to investigate if mannitol inhalation, as a model of exercise-induced bronchoconstriction (EIB), causes mast cell activation and release of mediators of bronchoconstriction.Urinary excretion of previously identified mediators of EIB was investigated in association with mannitol-induced bronchoconstriction. Twelve asthmatic and nine nonasthmatic subjects inhaled mannitol and urine was collected 60 min before and for 90 min after challenge. The urinary concentrations of leukotriene (LT)E 4 , the prostaglandin (PG)D 2 metabolite and the mast cell marker 9a,11b-PGF 2 were measured by enzyme immunoassay. N t -methylhistamine was measured by radioimmunoassay.In asthmatic subjects, inhalation of a mean¡SEM dose of 272¡56 mg mannitol induced a reduction in forced expiratory volume in one second (FEV1) of 34.5¡2.1%. This was associated with increases in urinary 9a,11b-PGF 2 (91.9¡8.2 versus 66.9¡ 6.6 ng?mmol creatinine -1 , peak versus baseline) and LTE 4 (51.3¡7.5 versus 32.9¡4.7). In nonasthmatic subjects, the reduction in FEV1 was 1.0¡0.5% after inhaling 635 mg of mannitol. Although smaller than in the asthmatics, significant increases of urinary 9a,11b-PGF 2 (68.4¡6.9 versus 56.0¡5.8 ng?mmol creatinine -1 ) and LTE 4 (58.5¡5.3 versus 43.0¡3.3 ng?mmol creatinine -1 ) were observed in the nonasthmatic subjects. There was also a small increase in urinary excretion of N t -methylhistamine in the nonasthmatics, but not in the asthmatics.The increased urinary levels of 9a,11b-prostaglandin F 2 support mast cell activation with release of mediators following inhalation of mannitol. Increased bronchial responsiveness to the released mediators could explain the exclusive bronchoconstriction in asthmatic subjects. Eur Respir J 2003; 22: 491-496.

Increased urinary leukotriene E4 concentration in patients with eosinophilic pneumonia

“…The urinary LTE 4 concentration increased in asthmatic patients during the early asthmatic response after allergen challenge [21], in exercise-induced asthma patients during bronchoconstriction [22] and in aspirin-intolerant asthma after aspirin provocation [18]. However, none of the EP patients who participated in the present study, despite their asthma complications, experienced an asthmatic exacerbation or showed any symptoms of airway narrowing.…”

The Effect of Omega-3 Fatty Acids on Bronchial Hyperresponsiveness, Sputum Eosinophilia, and Mast Cell Mediators in Asthma

“…There is strong evidence that the airway response to mannitol closely mimics central components of EIB, such as the activation of mast cells and eosinophils, resulting in the release of bronchoconstrictive mediators. 7,[9][10][11][12][13]19,20 However, the diff erences may lie in the intensity of the stimulus to the airways. Th e studies showing benefi t performed the exercise challenge until volitional exhaustion, which is a test that has a known low sensitivity to identifying EIB and which may induce milder airway responses in those with EIB.…”

“…Slower recovery from mannitol challenge does suggest a direct role of leukotrienes. 10,19 One study in humans has demonstrated worsening of daily peak fl ow and increased b 2 -agonist use with longer treatment of a daily dose of 3 g omega-3 fatty acids over 6 weeks in subjects with asthma and aspirin sensitivity. 24 Th e presumed mechanism for explaining the possible benefi cial eff ects of omega-3 fatty acids on infl ammatory pathways is through diversion of the production of bronchoconstricting prostaglandins and leukotrienes from the omega-6 substrate arachidonic acid to mediators biosynthesized from the alternative omega-3 substrates.…”

Design, Characterization, and Aerosol Dispersion Performance Modeling of Advanced Spray-Dried Microparticulate/Nanoparticulate Mannitol Powders for Targeted Pulmonary Delivery as Dry Powder Inhalers

“…The detailed mechanisms are described in the literature. (29)(30)(31)(32)(33)(34) A DPI formulation of mannitol as a marketed pharmaceutical product (Bronchitol TM ) is approved in Europe and has been very recently approved in the United States. The polymorphic system of D-mannitol has been well documented.…”