title: 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 beta(2)-agonists in as few as 7 days. Desensitization of beta(2)-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 beta(2)-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 FEV(1), 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 microgram, 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 FEV(1) 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 microgram/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 FEV(1) (2.77 +/- 0.18 vs 2.97 +/- 0.20 L; P =.014). Baseline FEV(1) 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).
  
  
  CONCLUSIONS
  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(1) 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 beta(2)-agonist treatment and could contribute to the deterioration of asthma control that is associated with regular use of beta(2)-agonist by potentiating allergic inflammation.
authors.affiliation: Division of Respiratory Medicine, Royal University Hospital, Departments of Physiology and Veterinary Microbiology, University of Saskatchewan, Saskatoon.
authors.forename: V A
authors.initials: VA
authors.lastname: Swystun
authors.forename: J R
authors.initials: JR
authors.lastname: Gordon
authors.forename: E B
authors.initials: EB
authors.lastname: Davis
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: D W
authors.initials: DW
authors.lastname: Cockcroft
mesh_terms: D000328:Adult; D000420:Albuterol / Q000627:therapeutic use*; D000485:Allergens; D001249:Asthma / Q000276:immunology*; D001985:Bronchial Provocation Tests; D001993:Bronchodilator Agents / Q000627:therapeutic use*; D053818:Chymases; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000201:enzymology*; D008875:Middle Aged; D012697:Serine Endopeptidases / Q000378:metabolism*; D013183:Sputum / Q000737:chemistry; D053802:Tryptases
chemical_list: D000485:Allergens; D001993:Bronchodilator Agents; D012697:Serine Endopeptidases; C083294:chymase 2; D053818:Chymases; D053802:Tryptases; D000420:Albuterol