Aspirin causes bronchoconstriction in aspirin-intolerant asthma (AIA) patients by triggering cysteinyl-leukotriene (cys-LT) production, probably by removing PGE2-dependent inhibition. To investigate why aspirin does not cause bronchoconstriction in all individuals, we immunostained enzymes of the leukotriene and prostanoid pathways in bronchial biopsies from AIA patients, aspirin-tolerant asthma (ATA) patients, and normal (N) subjects. 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 N biopsies (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 cys-LT levels in bronchoalveolar lavage (BAL) fluid of AIA patients correlated uniquely with bronchial counts of LTC4 synthase+ cells (rho = 0.83, P = 0.01). 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 = 0.007). Bronchial responsiveness to lysine-aspirin correlated exclusively with LTC4 synthase+ cell counts (rho = -0.63, P = 0.049, 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.

We have shown that inhalation of lysine aspirin enhances leukotriene production in the lungs of patients with aspirin-induced asthma (AIA). To assess the specificity of this reaction, we compared two well-matched groups of patients: eleven with AIA versus 14 asthmatics tolerant to aspirin (ATA). All subjects underwent bronchoalveolar lavage (BAL) with saline followed immediately by instillation of 10 mg of lysine aspirin, into a right middle lobe segmental bronchus, which was lavaged 15 min later. At baseline the two groups did not differ with respect to BAL fluid concentrations of cyclooxygenase products, peptido-leukotrienes, histamine, tryptase, interleukin-5 (IL-5), eosinophil cationic protein (ECP), or eosinophil number. Fifteen minutes after aspirin instillation, there was a statistically significant rise in peptido-leukotrienes, IL-5, and eosinophil number in AIA, but not in ATA, but not in ATA patients. In the former, but not in the latter group, mean histamine concentrations rose in response to aspirin, approaching the level of statistical significance. Tryptase and ECP levels showed no significant change. Aspirin significantly depressed PGE2 and thromboxane B2 (TXB2) in both groups, however PGD2, PGF2 alpha, and 9 alpha, 11 beta-PGF2 decreased only in ATA patients. A characteristic disturbance in eicosanoid balance, produced by aspirin in patients intolerant to this drug, might explain precipitation of asthma attacks.

We have recently shown that oral aspirin provocation leads to an increase in LTE4 and a reduction in 11-dehydro-TXB2 levels in urine of patients with aspirin induced-asthma (AIA). To test the hypothesis that cyclooxygenase inhibition and an enhancement of cysteinyl-leukotriene production occurs in the lungs of patients with AIA, we examined the eicosanoid levels in bronchoalveolar lavage fluid obtained 30 min after lysine-aspirin or placebo inhalation in 10 patients with AIA. Eosinophil cationic protein (ECP) levels were determined to evaluate eosinophil activation. Six asthmatics nonsensitive to aspirin (NA) underwent challenge with placebo. The dose of lysine-aspirin inhaled by patients with AIA was equal to that which had produced > or = 20% fall in FEV1. Compared with NA, patients with AIA had: (1) eicosanoid levels, particularly PGE2 and TXB2, elevated and (2) higher number of eosinophils and ECP. The overproduction of eicosanoids could be related to a distinct eosinophilic inflammation in airways of patients with AIA. Inhalation of lysine-aspirin had no effects on 12-HETE and 15-HETE levels, but it markedly depressed cyclooxygenase products and significantly enhanced leukotriene production in the lungs of patients with AIA.

The prevalence of AIA in Poland is 4.3%, being somewhat lower than in Finland and Australia, where it was recently reported to account for 8.8 and 10.9% of the adult asthmatics, respectively. These figures indicate that aspirin hypersensitivity might be a significant community problem.

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