Cowburn A S, Sladek K, Soja J, Adamek L, Nizankowska E, Szczeklik A, Lam B K, Penrose J F, Austen F K, Holgate S T, Sampson A P
University Medicine, Immunopharmacology Group, Southampton General Hospital, Southampton, SO16 6YD, United Kingdom.
J Clin Invest. 1998 Feb 15;101(4):834-46. doi: 10.1172/JCI620.
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.
阿司匹林通过触发半胱氨酰白三烯（cys-LT）生成，可能是通过消除前列腺素E2依赖性抑制作用，从而在阿司匹林不耐受性哮喘（AIA）患者中引起支气管收缩。为了研究为什么阿司匹林并非在所有个体中都引起支气管收缩，我们对AIA患者、阿司匹林耐受性哮喘（ATA）患者和正常（N）受试者的支气管活检组织中的白三烯和前列腺素途径的酶进行了免疫染色。表达cys-LT合成末端酶LTC4合酶的细胞计数在AIA活检组织（11.5±2.2个细胞/mm2，n = 10）中比ATA活检组织（2.2±0.7，n = 10；P = 0.0006）高5倍，比N活检组织（0.6±0.4，n = 9；P = 0.0002）高18倍。5-脂氧合酶、其激活蛋白（FLAP）、LTA4水解酶、环氧化酶（COX）-1和COX-2的免疫染色无差异。AIA患者支气管肺泡灌洗（BAL）液中基础cys-LT水平升高与支气管LTC4合酶阳性细胞计数唯一相关（rho = 0.83，P = 0.01）。赖氨酸-阿司匹林激发试验使AIA患者的BAL液中释放出额外的cys-LTs（200±120 pg/ml，n = 8），但ATA患者未释放（0.7±5.1，n = 5；P = 0.007）。支气管对赖氨酸-阿司匹林的反应性仅与LTC4合酶阳性细胞计数相关（rho = -0.63，P = 0.049，n = 10）。阿司匹林可能在所有受试者中消除了前列腺素E2依赖性抑制作用，但只有在AIA患者中，LTC4合酶在支气管中的表达增加才使得cys-LTs大量过量生成，从而导致支气管收缩。
