Aspirin-tolerant asthmatics generate more lipoxins than aspirin-intolerant asthmatics.
Asthma is characterized by chronic airway inflammation resulting from overproduction of pro-inflammatory mediators, such as leukotrienes (LT). The authors questioned the biosynthetic capacity of asthmatic patients for lipoxins (LX) and 15-epimer lipoxins (15-epi-LX), endogenous regulators of inflammatory responses that inhibit pro-inflammatory events. Levels of LXA4, 15-epi-LXA4 and LTC4 were determined in 14 clinically characterized aspirin-intolerant asthmatics (AIA), 11 aspirin-tolerant asthmatics (ATA) and eight healthy volunteers using a stimulated whole blood protocol. Both LXA4 and 15-epi-LXA4 were generated in whole blood activated by the divalent cation ionophore, A23187. Higher levels of LXA4 were produced in ATA than either AIA or healthy volunteers. Exposure of AIA whole blood to interleukin-3 prior to A23187 did not elevate their reduced capacity to generate LXA4. Generation of a bronchoconstrictor, LTC4, was similar in both AIA and ATA. Consequently, the ratio of LXA4:LTC4 quantitatively favoured the bronchoconstrictor for AIA and differed from both ATA and healthy subjects. In addition, the capacity for 15-epi-LXA4 generation was also diminished in AIA, since whole blood stimulated in the presence of aspirin gave increased levels only in samples from ATA. The present results indicate that asthmatics possess the capacity to generate 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 represents a novel paradigm for the development of chronic inflammatory disorders.
Dept of Medicine, Jagellonian University School of Medicine, Kraków, Poland.
M
M
Sanak
B D
BD
Levy
C B
CB
Clish
N
N
Chiang
K
K
Gronert
L
L
Mastalerz
C N
CN
Serhan
A
A
Szczeklik
D000328:Adult; D001241:Aspirin / Q000009:adverse effects*; D001249:Asthma / Q000139:chemically induced / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis*; D017997:Leukotriene C4 / Q000096:biosynthesis; D044045:Lipoxins; D008297:Male; D008875:Middle Aged; D013237:Stereoisomerism
D006893:Hydroxyeicosatetraenoic Acids; D044045:Lipoxins; C040527:lipoxin A4; D017997:Leukotriene C4; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; C042651:lipoxin B4; D001241:Aspirin