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Published ahead of print on June 16, 2005, doi:10.1164/rccm.200410-1413OC

Am. J. Respir. Crit. Care Med., Volume 172, Number 7, October 2005, 824-830

A more recent version of this article appeared on October 1, 2005
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Submitted on October 26, 2004
Accepted on June 14, 2005

Diminished Lipoxin Biosynthesis in Severe Asthma

Bruce D Levy1*, Caroline Bonnans1, Eric S Silverman2, Lyle J Palmer3, Gautham Marigowda1, and Elliot Israel1

1 Pulmonary and Critical Care Medicine and Partners Asthma Center, Department of Internal Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, United States, 2 Pulmonary Physiology Program, Harvard School of Public Health, Boston, MA, USA, 3 UWA Centre for Medical Research, University of Western Australia, Perth, Australia

* To whom correspondence should be addressed. E-mail: blevy{at}partners.org.

Rationale and Objectives: Severe asthma is characterized by increased airway inflammation that persists despite therapy with corticosteroids. Not merely an exaggeration of the eosinophilic inflammation that characterizes mild to moderate asthma, unique features are present in severe disease. Although arachidonic acid metabolism is well appreciated to regulate airway inflammation and reactivity, alterations in the biosynthetic capacity for both pro- and anti-inflammatory eicosanoids in severe asthma have not been determined. Methods: Patients with severe asthma were identified according to the NHLBI Severe Asthma Research Program criteria. Samples of whole blood from individuals with severe or moderate asthma were assayed for biosynthesis of lipoxygenase-derived eicosanoids. Measurements and Main Results: The counter-regulatory 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 to 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 pro-phlogistic cysteinyl leukotrienes were increased in samples from severe compared to moderate asthma (112.5 [SD 53.7] pg/ml vs. 64.4 [SD 24.8] pg/ml, P=0.03). Basal circulating levels of LXA4 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 alternate therapeutic strategy that emphasizes natural counter-regulatory pathways in the airway.
Key words: Eicosanoids, Inflammation Mediators, Biosynthesis, Chromatograpy, High Pressure Liquid




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