Diminished lipoxin biosynthesis in severe asthma.
OBJECTIVE
Severe asthma is characterized by increased airway inflammation that persists despite therapy with corticosteroids. It is not, however, merely an exaggeration of the eosinophilic inflammation that characterizes mild to moderate asthma; rather, severe asthma presents unique features. Although arachidonic acid metabolism is well appreciated to regulate airway inflammation and reactivity, alterations in the biosynthetic capacity for both pro- and antiinflammatory eicosanoids in severe asthma have not been determined.


METHODS
Patients with severe asthma were identified according to National Heart, Lung, and Blood Institute Severe Asthma Research Program criteria. Samples of whole blood from individuals with severe or moderate asthma were assayed for biosynthesis of lipoxygenase-derived eicosanoids.


RESULTS
The counterregulatory mediator lipoxin A4 was detectable in low picogram amounts, using a novel fluorescence-based detection system. In activated whole blood, mean lipoxin A4 levels were decreased in severe compared with moderate asthma (0.4 [SD 0.4] ng/ml vs. 1.8 [SD 0.8] ng/ml, p=0.001). In sharp contrast, mean levels of prophlogistic cysteinyl leukotrienes were increased in samples from severe compared with moderate asthma (112.5 [SD 53.7] pg/ml vs. 64.4 [SD 24.8] pg/ml, p=0.03). Basal circulating levels of lipoxin A4 were also decreased in severe relative to moderate asthma. The marked imbalance in lipoxygenase-derived eicosanoid biosynthesis correlated with the degree of airflow obstruction.


CONCLUSIONS
Mechanisms underlying airway responses in severe asthma include underproduction of lipoxins. This is the first report of a defect in lipoxin biosynthesis in severe asthma, and suggests an alternative therapeutic strategy that emphasizes natural counterregulatory pathways in the airways.
Levy
Bruce D
BD
Pulmonary and Critical Care Medicine and Partners Asthma Center, Department of Internal Medicine, PBB-Clinics-3, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA. blevy@partners.org
Bonnans
Caroline
C
Silverman
Eric S
ES
Palmer
Lyle J
LJ
Marigowda
Gautham
G
Israel
Elliot
E
D000328:Adult; D001249:Asthma / Q000378:metabolism* / Q000503:physiopathology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D044045:Lipoxins / Q000096:biosynthesis*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D018077:Receptors, Leukotriene / Q000378:metabolism; D013183:Sputum / Q000737:chemistry
D044045:Lipoxins; D008565:Membrane Proteins; D018077:Receptors, Leukotriene; C040527:lipoxin A4; C083169:leukotriene D4 receptor