Background In asthma, cysteinyl leukotrienes (CysLTs) play varying roles in the bronchomotor response to multiple provocative stimuli. The contribution of CysLTs on the airway's response to hypertonic saline (HS) inhalation in asthma is unknown. Whether polymorphisms in the leukotriene biosynthetic pathway affect the contribution of CysLTs to this response is also unknown. Methods In a prospective, randomized, double blind, placebo-controlled cross-over study, mild and moderate asymptomatic asthmatics underwent inhaled 3% HS challenge by doubling the duration of nebulization (0.5, 1, 2, 4, and 8 min) two hours after one dose of montelukast (a CysLT receptor 1 [CysLTR1] antagonist) or placebo, and after three week courses. We examined the effect of the leukotriene C4 synthase (LTC4S) polymorphism (A-444C) on the efficacy of montelukast against HS inhalation in an exploratory manner. Results In 37 subjects, two hours after administration of montelukast, the mean provocative dose of HS required to cause a 20% drop in FEV1 (HS-PD20) increased by 59% (9.17 after placebo vs. 14.55 ml after montelukast, p = 0.0154). Three weeks of cysLTR1 antagonism increased the HS-PD20 by 84% (10.97 vs. 20.21 ml, p = 0.0002). Three weeks of CysLTR1 antagonism appeared to produce greater effects on blocking bronchial hyper responsiveness (two hour vs. three week HS-PD20 values 14.55 vs. 20.21 ml respectively, p = 0.0898). We did not observe an effect of the LTC4S polymorphism on the response to CysLTR1 antagonism in this cohort. Conclusions A significant proportion of HS-induced bronchoconstriction is mediated by release of leukotrienes as evidenced by substantial acute inhibition with a CysLTR1 antagonist. There was a trend toward greater inhibition of bronchial responsiveness with three weeks of therapy as opposed to acute CysLTR1 antagonism.

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AimStudies have reported contradictory results on the relationship between airway hyperresponsiveness to methacholine (Mch) and that elicited by hypertonic saline (HS) inhalation. We investigated the correlation between Mch-PC20 and HS-PD20 in mild asthmatics who had performed both challenges in a research setting.MethodsWe assembled data on mild asthmatics on prn b-agonists, with a history of positive response to Mch (PC20 ≥ 8 mg/mL), who had undergone a staged 3% saline challenge. Mean time between challenges was 23 months (range 0.1-74, SD 21). We also compared the bronchial reactivity to exhaled breath condensate (EBC) pH, a putative marker of airway inflammation.ResultsSubject data: Of the 24 subjects, 16 (67%) were responsive to the HS challenge. Nonresponders were assigned an HS-PD20 value of 74 mL. HS-PD20 correlated significantly with Mch-PC20 (r = .52, p = .0089). EBC pH did not have a significant relationship with either HS-PD20 or Mch-PC20.ConclusionHS and Mch reactivity provide similar assessments of airway reactivity in asthmatics not on controller medications. Considering the stability of the correlation, these data suggest that HS may be a substitute for Mch challenge. Neither measure of hyperresponsiveness correlates with EBC pH.