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Patients & Consumers Conditions En Español Find an Allergist / Immunologist Just for Kids New Research Parent Resources Pollen Levels Publications Real Life Stories Request a Speaker School Tools Seniors The Virtual Allergist™ Treatments Search by Condition (A-Z) Search by Topic Allergy & Asthma Issues Educational Brochures Elements of Allergy and Asthma Order Public Education Materials Washington Post Supplement Allergy Shots Drug Guide Sublingual Immunotherapy (SLIT)		SELECTED ARTICLES FROM THE RECENT LITERATURE 2008 10/16/2008 Severe asthma characterized by effective synthesis of lipoxin A4 and diminished numbers of lipoxin A4 receptors Summary The investigators of this multicenter study of arachidonic acid metabolism in subjects with severe asthma, non-severe asthma, and non-asthmatics. They measured levels of arachidonic acid metabolites in bronchoalveolar lavage fluid and studied the expression of lipoxin biosynthetic genes in whole blood, bronchoalveolar lavage cells, and endobronchial biopsies. They also evaluated the expression of leukocyte lipoxin A4 receptors. Cysteinyl leukotrienes were elevated in non-severe and severe asthmatics. Their levels were independent of severity, and thus did not distinguish between the two groups of asthmatics. In contrast, bronchoalveolar lavage fluid lipoxins were significantly diminished in severe asthmatics compared to the non-severe group, and thus distinguished the two asthmatic populations. There also was a decreased ratio of bronchoalveolar lavage fluid lipoxin A4 to cysteinyl leukotrienes, and this "sharply distinguished" severe from non-severe asthma. The diminished lipoxin levels in the severe group were related to diminished expression of lipoxygenase biosynthetic genes. Accompanying the diminished levels of lipoxins, there was a decreased expression of lipoxin A4 receptors in granulocytes in the severe group. The authors concluded that "severe asthma is characterized, in part, by defective lipoxin counter-regulatory signaling circuits." Editor's comment: Lipoxins are products of arachidonic acid metabolism that differ in structure and function from cysteinyl leukotrienes and leukotriene B4. They are anti-inflammatory molecules and can protect from cysteinyl leukotriene mediated bronchoconstriction. It has been previously shown that subjects with severe asthma have diminished peripheral blood lipoxin A4 levels, and decreased expression of 15-lipoxygenase-1, the enzyme that catalyzes lipoxin A4 synthesis. This is the first study to demonstrate that a similar defect exists in the airways of severe asthmatics. Moreover, the authors found a reduced expression of lipoxin A4 receptors in severe asthma. Both the reduced amount of lipoxin A4 and the diminished numbers of lipoxin receptors distinguished severe asthmatics from the non severe group better than the levels of cysteinyl leukotrienes. Another important observation of this study is that in severe asthmatics, corticosteroid administration did not appear to correct the diminished expression of lipoxin A4 or the enzyme, 15-lipoxygenase-1, responsible for its synthesis. This is consistent with the clinically observed resistance to corticosteroids found in severe asthmatics. Thus defective lipoxin and lipoxin receptor generation may be a unique characteristic of severe asthma, distinguishing it from less severe disease and perhaps accounting for a degree of steroid resistance. In summary, this investigation incriminates a dysregulation of lipoxin synthesis as well as a diminished expression of lipoxin A4 receptor as a feature distinguishing severe from non-severe asthma. This implies that the difference between these two groups may be qualitative as well as quantitative. They also found that this defect does not appear to be responsive to corticosteroid therapy, thus implying a future role for therapy with lipoxin A4 analogs. Reference Planaguma A, et al. Airway lipoxin A4 generation and lipoxin A4 receptor expression are decreased in severe asthma. American Journal of Respiratory and Critical Care Medicine 2008; 178:574-582.   Back
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