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.