Mast cell tryptase release and asthmatic responses to allergen increase with regular use of salbutamol

Abstract

Background: Increased asthmatic responses to allergen, both early and late, have been demonstrated after regular use of β2-agonists in as few as 7 days. Desensitization of β2-adrenergic receptors on airway mast cells may contribute to this effect by allowing greater release of mast cell mediator on allergen-induced degranulation. Tryptase released from lung mast cells can be measured in serum 1 hour after allergen challenge and serves as a marker of mast cell degranulation. Objective: To examine the effect of regular treatment with salbutamol, a β2-agonist, on mast cell mediator release after allergen challenge and its influence on the early asthmatic response (EAR) and the late allergic response, we measured the EAR, serum tryptase levels, the 7-hour FEV1, and sputum tryptase levels and cell profiles. Methods: We conducted a placebo-controlled, double-blind, randomized cross- over comparison of treatments for 10 days with either a salbutamol metered- dose inhaler (100 μg, 2 puffs 4 times daily) or a matched placebo inhaler with at least a 7-day washout between treatments. Atopic subjects (n = 14) with mild-to-moderate asthma performed same-dose allergen inhalation tests after both treatments 12 to 15 hours after the last dose of study inhaler. Baseline and 7-hour FEV1 and the EAR to allergen were measured by using spirometry; venous blood was drawn at 1 hour for analysis of serum tryptase; and sputum was induced and collected at 1 and 7 hours. Results: Salbutamol treatment resulted in a significantly greater EAR (20% ± 1.6% [SEM] vs 15% ± 2.1%; P = .047); increased 1-hour serum tryptase levels (9.09 ± 1.57 vs 7.52 ± 1.12 μg/L; P = .011); increased proportions of eosinophils in the 7- hour sputum sample (39.1% ± 5.1% vs 28.4% ± 4.4%; P < .05); increased proportion of metachromatic cells in the 7-hour sputum sample (4.4% ± 1.1% vs 2.2% ± 0.6%; P = .032); and lower 7-hour FEV1 (2.77 ± 0.18 vs 2.97 ± 0.20 L; P = .014). Baseline FEV1 was not significantly different after salbutamol treatment compared with values after placebo treatment (2.90 ± 0.20 vs 3.00 ± 0.19 L; P = .11). Conclusion: Regular 10-day treatment with salbutamol increases the allergen-induced release of mediator from airway mast cells, and this is reflected in an increased EAR to allergen. Late-phase responses to allergen were also enhanced, as demonstrated by decreased 7-hour FEV↓ and increased eosinophilia and percentage of metachromatic cells in the 7-hour sputum sample. Increased allergen-induced mast cell degranulation could, in part, explain the increased asthmatic responses to allergen after β2-agonist treatment and could contribute to the deterioration of asthma control that is associated with regular use of β2-agonist by potentiating allergic inflammation.