Airway Lipoxin A4Generation and Lipoxin A4Receptor Expression Are Decreased in Severe Asthma

• DOI: 10.1164/rccm.200801-061oc
• Publication Date: 2008-06-27T01:38:07Z
• Authors: Anna Planagumà; Shamsah Kazani; Gautham Marigowda; Oliver Haworth; Thomas J. Mariani; Elliot Israel; Eugene R. Bleecker; Douglas Curran-Ev...; Serpil C. Erzurum; William J. Calhoun; Mario Castro; Kian Fan Chung; Benjamin Gaston; Nizar N. Jarjour; William W. Busse; Sally E. Wenzel; Bruce D. Levy
• Keywords: Pulmonary and Respiratory Medicine; Adult; Male; 0303 health sciences; 610; Bronchi; Middle Aged; Critical Care and Intensive Care Medicine; Flow Cytometry; Polymerase Chain Reaction; Receptors, Formyl Peptide; Asthma; 3. Good health; Lipoxins; 03 medical and health sciences; Hydroxyeicosatetraenoic Acids; Humans; Female; Receptors, Lipoxin; Bronchoalveolar Lavage Fluid

Airway inflammation is common in severe asthma despite antiinflammatory therapy with corticosteroids. Lipoxin A(4) (LXA(4)) is an arachidonic acid-derived mediator that serves as an agonist for resolution of inflammation.Airway levels of LXA(4), as well as the expression of lipoxin biosynthetic genes and receptors, in severe asthma.Samples of bronchoalveolar lavage fluid were obtained from subjects with asthma and levels of LXA(4) and related eicosanoids were measured. Expression of lipoxin biosynthetic genes was determined in whole blood, bronchoalveolar lavage cells, and endobronchial biopsies by quantitative polymerase chain reaction, and leukocyte LXA(4) receptors were monitored by flow cytometry.Individuals with severe asthma had significantly less LXA(4) in bronchoalveolar lavage fluids (11.2 +/- 2.1 pg/ml) than did subjects with nonsevere asthma (150.1 +/- 38.5 pg/ml; P < 0.05). In contrast, levels of cysteinyl leukotrienes were increased in both asthma cohorts compared with healthy individuals. In severe asthma, 15-lipoxygenase-1 mean expression was decreased fivefold in bronchoalveolar lavage cells. In contrast, 15-lipoxgenase-1 was increased threefold in endobronchial biopsies, but expression of both 5-lipoxygenase and 15-lipoxygenase-2 in these samples was decreased. Cyclooxygenase-2 expression was decreased in all anatomic compartments sampled in severe asthma. Moreover, LXA(4) receptor gene and protein expression were significantly decreased in severe asthma peripheral blood granulocytes.Mechanisms underlying pathological airway responses in severe asthma include lipoxin underproduction with decreased expression of lipoxin biosynthetic enzymes and receptors. Together, these results indicate that severe asthma is characterized, in part, by defective lipoxin counterregulatory signaling circuits.