Purpose of the Study
To gain a better understanding of why aspirin does not cause bronchoconstriction in all individuals, as it does in patients with aspirin-intolerant asthma (AIA).
Ten patients with AIA (n = 10), 10 patients with aspirin-tolerant asthma (ATA), and 9 nonatopic, normal subjects were included in this investigation. All subjects were nonsmokers and clinically stable at the time of the study.
Bronchial responsiveness to inhaled lys-aspirin was assessed with a dosimeter-controlled nebulizer using a standard protocol. Bronchoscopy and bronchoalveolar lavage (BAL) were carried out according to the American Thoracic Society guidelines. Using the bronchial biopsy specimens, enzymes of the leukotriene and prostanoid pathways were immunostained; standard BAL fluid mediator assays were also undertaken.
Counts of cells expressing the terminal enzyme for cys-LT synthesis, LTC4 synthase, were fivefold higher in AIA biopsies (11.5 ± 2.2 cells/mm2, n = 10) than in ATA biopsies (2.2 ± 0.7, n = 10; P = 0.0006) and 18-fold higher than in biopsies from normal controls (0.6 ± 0.4, n = 9; P = 0.0002). Immunostaining for 5-lipoxygenase, its activating protein (FLAP), LTA4 hydrolase, cyclooxygenase (COX)-1 and COX-2 did not differ. Enhanced baseline cyc-LYT4 synthase+ cells (p = 0.83, P= .01). Lysine-aspirin challenge released additional cys-LTs into BAL fluid in AIA patients (200 ± 120 pg/mL, n = 8) but not in ATA patients (0.7 ± 5.1, n = 5; P = .007). Bronchial responsiveness to lysine-aspirin correlated exclusively with LTC4 synthase+ cell counts (p = −0.63,P = .049, n = 10).
Aspirin may remove PGE2-dependent suppression in all subjects, but only in AIA patients does increased bronchial expression of LTC4 synthase allow marked overproduction of cys-LTs leading to bronchoconstriction.
Although we now have leukotriene-modifying medications that can be particularly useful in the management of chronic asthma in patients with AIA, a complete mechanistic understanding of this disease has been lacking. This investigation provides novel insights into the pathogenesis of AIA, which may be present in up to 20% of children and adults with asthma. In bronchial biopsy specimens, the investigators reported a dramatic overrepresentation of cells expressing LTC4 synthase in the AIA patients, as compared with the ATA patients and normal control subjects. This basic difference may provide a basis for the chronic overproduction and for the aspirin-induced increments in cys-LT production in AIA, and for the lack of adverse responses to NSAIDs in ATA and normal individuals. Hopefully, further research in this area will help sort out the clinical heterogeneity that is typical in this group of patients (ie, some AIA patients only reacting to aspirin, while others with AIA may react to aspirin and the whole spectrum of nonsteroidal anti-inflammatory drugs (NSAIDs).