Aspirin-tolerant asthmatics generate more lipoxins than aspirin-intolerantasthmatics

Asthma is characterized by chronic airway inflammation resulting from overp roduction of pro-inflammatory mediators, such as leukotrienes (LT), The aut hors questioned the biosynthetic capacity of asthmatic patients for lipoxin s (LX) and 15-epimer lipoxins (15-epi-LX), endogenous regulators of inflamm atory responses that inhibit pro-inflammatory events, Levels of LXA(4), 15-epi-LXA(4) and LTC4 were determined in 14 clinically c haracterized aspirin-intolerant asthmatics (AIA), 11 aspirin-tolerant asthm atics (ATh) and eight healthy volunteers using a stimulated whole blood pro tocol, Both LXA(4) and 15-epi-LXA(4) were generated in whole blood activated by th e divalent cation ionophore, A23187, Higher levels of LXA(4) were produced in ATA than either AIA or healthy volunteers, Exposure of AIA whole blood t o interleukin-3 prior to A23187 did not elevate their reduced capacity to g enerate LXA(4). Generation of a bronchoconstrictor, LTC4, was similar in bo th AIA and ATA, Consequently, the ratio of LXA(4):LTC4 quantitatively favou red the bronchoconstrictor for AIA and differed from both ATA and healthy s ubjects. In addition, the capacity for 15-epi-LXA(4) generation was also di minished in AIA, since whole blood stimulated in the presence of aspirin ga ve increased levels only in samples from ATA, The present results indicate that asthmatics possess the capacity to genera te both lipoxins and 15-epimer-lipoxins, but aspirin-intolerant asthmatics display a lower biosynthetic capacity than aspirin-tolerant asthmatics for these potentially protective lipid mediators. This previously unappreciated , diminished capacity for lipoxin formation by aspirin-intolerant asthmatic patients may contribute to their more severe clinical phenotype, and repre sents a novel paradigm for the development of chronic inflammatory disorder s.