title: Direct evidence for a role of the mast cell in the nasal response to aspirin in aspirin-sensitive asthma.
abstract: BACKGROUND
  A subset of patients with asthma experience adverse nasoocular reactions after ingestion of aspirin or agents that inhibit cyclooxygenase. Recent evidence has implicated the leukotrienes in the nasoocular reaction, but the cellular sources and mechanism of activation are unknown. We used nasal lavage with and without a 5-lipoxygenase inhibitor, zileuton, to define the role of leukotrienes and to profile nasal cellular activation during this reaction.
  
  
  METHODS
  A group of eight patients with asthma shown to have adverse reactions to aspirin documented by a 15% or greater decrease in forced expiratory volume in 1 second, accompanied by an elevation in urinary leukotriene E4 after ingestion of aspirin, received aspirin or placebo in a study with a crossover design. Nasal symptoms and nasal tryptase, histamine, leukotriene, and eosinophil cationic protein levels were evaluated. Serum tryptase and urinary histamine levels were also assessed. Subjects were then randomized to receive a week of treatment with zileuton or placebo, according to a double-blind, crossover design followed by aspirin challenge and measurement of the same mediators.
  
  
  RESULTS
  Aspirin ingestion produced a marked increase in nasal symptoms from a baseline symptom score of 2.1 +/- 0.7 to a maximum of 8.4 +/- 1.2 (p < 0.0007). Aspirin ingestion produced a mean maximal increase in nasal tryptase of 3.5 +/- 2.6 ng/ml, whereas placebo ingestion produced a mean maximal increase of 0.1 +/- 0.2 ng/ml (p < 0.05, aspirin vs placebo). Mean maximal nasal histamine increased 1.73 +/- 1.16 ng/ml versus 0.08 +/- 0.08 ng/ml from baseline (p < 0.05, aspirin vs placebo). Aspirin produced a mean maximal increase in nasal leukotriene value of 152 pg/ml versus a 16 pg/ml decrease after placebo ingestion (p < 0.05). Zileuton treatment blocked the increase in nasal symptoms after aspirin ingestion (maximum nasal symptom score of 1.6 +/- 0.6 with zileuton vs 5.5 +/- 0.9 with placebo [p < 0.0053]). It also blocked the rise in nasal tryptase (p = 0.011) and nasal leukotriene (p < 0.05) levels after aspirin ingestion. Zileuton treatment had no significant effect on the recovery of nasal histamine.
  
  
  CONCLUSIONS
  The increase in nasal symptoms in aspirin-sensitive patients with asthma after aspirin ingestion is associated with increases in nasal tryptase, histamine, and cysteinyl leukotriene levels. This mediator profile is consistent with mast cell activation during the nasal response to aspirin and suggests that 5-lipoxygenase products are essential for the nasal response to aspirin.
authors.affiliation: Combined Program in Pulmonary and Critical Care Medicine, Beth Israel Hospital, Boston, MA.
authors.forename: A R
authors.initials: AR
authors.lastname: Fischer
authors.forename: M A
authors.initials: MA
authors.lastname: Rosenberg
authors.forename: C M
authors.initials: CM
authors.lastname: Lilly
authors.forename: J C
authors.initials: JC
authors.lastname: Callery
authors.forename: P
authors.initials: P
authors.lastname: Rubin
authors.forename: J
authors.initials: J
authors.lastname: Cohn
authors.forename: M V
authors.initials: MV
authors.lastname: White
authors.forename: Y
authors.initials: Y
authors.lastname: Igarashi
authors.forename: M A
authors.initials: MA
authors.lastname: Kaliner
authors.forename: J M
authors.initials: JM
authors.lastname: Drazen
mesh_terms: D000328:Adult; D001241:Aspirin / Q000009:adverse effects*; D001249:Asthma / Q000378:metabolism*; D001798:Blood Proteins / Q000032:analysis; D053818:Chymases; D018592:Cross-Over Studies; D004311:Double-Blind Method; D047091:Eosinophil Granule Proteins; D005260:Female; D006632:Histamine / Q000032:analysis; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000494:pharmacology; D015289:Leukotrienes / Q000032:analysis; D008297:Male; D008407:Mast Cells / Q000502:physiology*; D008875:Middle Aged; D009297:Nasal Mucosa / Q000187:drug effects*; D012260:Ribonucleases; D012697:Serine Endopeptidases / Q000378:metabolism; D053802:Tryptases
chemical_list: D001798:Blood Proteins; D047091:Eosinophil Granule Proteins; D015289:Leukotrienes; D006632:Histamine; D012260:Ribonucleases; D012697:Serine Endopeptidases; C083294:chymase 2; D053818:Chymases; D053802:Tryptases; D001241:Aspirin; C063449:zileuton; D006918:Hydroxyurea