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

doi:10.1067/mai.2000.107396

Journal of Allergy and Clinical Immunology

Volume 106, Issue 1, Part 1, July 2000, Pages 57-64

https://doi.org/10.1067/mai.2000.107396 Get rights and content

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 FEV₁ 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. (J Allergy Clin Immunol 2000;106:57-64.)

Section snippets

Design

Sixteen subjects with asthma were enrolled in a randomized, double-blind, placebo-controlled, cross-over study to compare the effects of 10-day treatment periods each of salbutamol and placebo on the allergen-induced asthmatic responses. Treatments consisted of salbutamol (100 μg/puff, Ventolin; Glaxo Wellcome Inc, Mississauga, Ontario, Canada) or identical placebo metered-dose inhaler (2 puffs administered 4 times daily). All evaluated subjects completed both treatments. The second treatment

RESULTS

Two subjects were withdrawn from the study. Subject 3 was excluded because of an inability to withhold rescue inhaler use during the night before allergen challenges. Subject 16 was unable to complete the second treatment period because of a deterioration of asthma control that was coincident with the onset of spring mold sporing season. Subject 12 had no measurable serum tryptase. Thus there were evaluable data on 14 subjects for baseline FEV₁, 7-hour FEV₁, and EAR, and evaluable data on 13

DISCUSSION

We have demonstrated a significant increase in the serum tryptase 1 hour after a same-dose allergen challenge, along with a significant increase in the EAR to allergen after treatment with salbutamol in comparison with placebo. Salbutamol treatment was also associated with a lower FEV₁ and increased sputum eosinophil and metachromatic cell counts at 7 hours after bronchial allergen challenge.

Previous investigations have demonstrated the increased EAR to allergen after regular (4 times daily)

Acknowledgements

We acknowledge the invaluable contribution to the tryptase assay made by Dr Mark L. Salkie, MB, FRCPC, and Carol Cadrain, Departments of Pathology and Biochemistry, Royal University Hospital, Saskatoon, Saskatchewan.

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^☆: Supported by a grant from the Saskatchewan Lung Association.

^☆☆: Reprint requests: Donald W. Cockcroft, MD, FRCP, Royal University Hospital, Division of Respiratory Medicine, 5th Floor Ellis Hall, Saskatoon, SK S7N 0W8 Canada.

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Asthma, rhinitis, other respiratory diseasesMast cell tryptase release and asthmatic responses to allergen increase with regular use of salbutamol☆,☆☆

Abstract

Section snippets

Design

RESULTS

DISCUSSION

Acknowledgements

Lancet

J Allergy Clin Immunol

J Allergy Clin Immunol

Am J Med

Lancet

Lancet

Lancet

Respir Med

Chest

J Allergy Clin Immunol

J Allergy Clin Immunol

Immunol Today

J Biol Chem

Tolerance to the nonbronchodilator effects of inhaled β2-agonists in asthma

N Engl J Med

Long-term effects of a long-acting β2 adrenoceptor agonist, salmeterol, on airway hyperresponsiveness in patients with mild asthma

N Engl J Med

Effects of long-term treatment with inhaled corticosteroids and beta-agonists on the bronchial responsiveness in children with asthma

J Allergy Clin Immunol

Rebound increase in bronchial responsiveness after treatment with inhaled terbutaline

Lancet

The effect of regular inhaled albuterol on exercise-induced bronchoconstriction

Am J Respir Crit Care Med

Tolerance to the bronchoprotective effect of salmeterol in adolescents with exercise-induced asthma using concurrent inhaled glucocorticoid treatment

Pediatrics

Interaction of inhaled β2 agonist and inhaled corticosteroid on airway responsiveness to allergen and methacholine

Am J Respir Crit Care Med

Asthma, rhinitis, other respiratory diseases
Mast cell tryptase release and asthmatic responses to allergen increase with regular use of salbutamol☆,☆☆

Tolerance to the nonbronchodilator effects of inhaled β₂-agonists in asthma

Long-term effects of a long-acting β₂ adrenoceptor agonist, salmeterol, on airway hyperresponsiveness in patients with mild asthma

Interaction of inhaled β₂ agonist and inhaled corticosteroid on airway responsiveness to allergen and methacholine