Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma
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 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 (p = 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 (p = -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.
5-lipoxygenase, Aspirin, Asthma, Cyclooxygenase, Leukotriene C synthase
834-846
Cowburn, Andrew S.
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Sladek, Krzysztof
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Soja, Jerzy
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Adamek, Lukasz
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Nizankowska, Ewa
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Szczeklik, Andrzej
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Lam, Bing K.
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Penrose, John F.
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Austen, K. Frank
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Holgate, Stephen T.
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Sampson, Anthony P.
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15 February 1998
Cowburn, Andrew S.
265baf1a-3607-403d-9e09-46f0fb193a0c
Sladek, Krzysztof
e83e4e98-a761-4156-ac91-562a572a8381
Soja, Jerzy
cdabcb8d-fc04-42ac-8277-265edb1d8975
Adamek, Lukasz
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Nizankowska, Ewa
29680f35-b6b1-4601-ac80-f2fe6c0fbd43
Szczeklik, Andrzej
8cb2de10-5f5f-4cd8-a6b6-7ec2a8a46fb1
Lam, Bing K.
9ba75dc7-dc37-41ad-9554-17811aa52aa5
Penrose, John F.
a1d34fbc-ff46-49bd-a184-ba20a900239b
Austen, K. Frank
59cdb2b7-ff11-42a0-93db-44f643c065e1
Holgate, Stephen T.
2e7c17a9-6796-436e-8772-1fe6d2ac5edc
Sampson, Anthony P.
4ca76f6f-ff35-425d-a7e7-c2bd2ea2df60
Cowburn, Andrew S., Sladek, Krzysztof, Soja, Jerzy, Adamek, Lukasz, Nizankowska, Ewa, Szczeklik, Andrzej, Lam, Bing K., Penrose, John F., Austen, K. Frank, Holgate, Stephen T. and Sampson, Anthony P.
(1998)
Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma.
Journal of Clinical Investigation, 101 (4), .
(doi:10.1172/JCI620).
Abstract
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 (p = 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 (p = -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.
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Published date: 15 February 1998
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Copyright 2017 Elsevier B.V., All rights reserved.
Keywords:
5-lipoxygenase, Aspirin, Asthma, Cyclooxygenase, Leukotriene C synthase
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Local EPrints ID: 455202
URI: http://eprints.soton.ac.uk/id/eprint/455202
ISSN: 0021-9738
PURE UUID: a851268e-a20a-40b0-aa79-be8ad7fc8f82
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Date deposited: 15 Mar 2022 17:33
Last modified: 06 Jun 2024 01:35
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Author:
Andrew S. Cowburn
Author:
Krzysztof Sladek
Author:
Jerzy Soja
Author:
Lukasz Adamek
Author:
Ewa Nizankowska
Author:
Andrzej Szczeklik
Author:
Bing K. Lam
Author:
John F. Penrose
Author:
K. Frank Austen
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