Uncoupled regulation of leukotriene C sub(4) synthase in platelets from aspirin-intolerant asthmatics and healthy volunteers after aspirin treatment

• Published in: Clinical and experimental allergy 2002-11, Vol.32 (11), p.1566-1573
• Main Authors: Tornhamre, S, Ehnhage, A, Koelbeck, K G, Edenius, C, Lindgren, JA
• Format: Article
• Language: English
• ISSN: 0954-7894
• DOI: 10.1046/j.1365-2222.2002.01531.x

Background We have reported that thromboxane A sub(2) induces suppression of leukotriene (LT) C sub(4) synthase activity in human platelets. Aim In the present study, we describe a mechanism whereby aspirin treatment can lead to increased formation of LTC sub(4), which is a potent bronchoconstrictor and inflammatory mediator. This mechanism is also demonstrated to be present in platelets from aspirin-intolerant asthmatics (AIA). Methods The effect of arachidonic acid or platelet agonists on LTC sub(4) synthase activity was investigated in platelets obtained from healthy volunteers, aspirin-intolerant asthmatics or aspirin-tolerant asthmatics after in vivo treatment or in vitro pre-incubation with aspirin. Results Incubation of normal platelets with arachidonic acid or collagen provoked approximately 50% reduction of platelet LTC sub(4) synthase activity, as determined by the conversion of LTA sub(4) to LTC sub(4). However, the inhibitory effect of arachidonic acid or collagen was not observed after oral administration of aspirin prior to collection of the platelets. Arachidonic acid-induced inhibition of LTC sub(4) synthase activity was totally abolished in platelets collected from peripheral blood already 30 min after aspirin ingestion but was fully restored in platelets collected 3 to 7 days after the administration of aspirin. Treatment of platelet suspensions with aspirin in vitro dose-dependently counteracted the suppressive effect of arachidonic acid on LTC sub(4) formation, with total reversal at approximately 40 mu M. In contrast, the major aspirin metabolite, salicylic acid did not alter arachidonic acid-induced reduction of LTC sub(4) synthase activity. Similarly, LTC sub(4) synthase activity in platelets from AIA and aspirin-tolerant asthmatics (ATA) was reduced by approximately 50% after pre-treatment with arachidonic acid in vitro. Again the inhibitory effect was abolished when platelets were pre-incubated in the presence of aspirin. Conclusion The results indicate that oral aspirin administration can lead to uncoupling of thromboxane A sub(2)-dependent negative feedback mechanisms, which may normally restrict the production of cysteinyl leukotrienes. This mechanism can be of potential interest in aspirin-induced asthma.