Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma

Aspirin causes bronchoconstriction in aspirin-intolerant asthma (AIA) patients by triggering cysteinyl-leukotriene (cys-LT) production, probably by removing PGE(2)-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, LTC, synthase, were fivefold higher in AIA biopsies (11.5+/-2.2 cells/mm(2), 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), LTA(4) 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 LTC, synthase(+) cells (p = 0.83, P = 0.01), Lysine-aspirin challenge released additional cys-LTs into BAL fluid in ALA 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 (p = -0.63, P = 0.049, n = 10), Aspirin may remove PGE(2)-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.