Published ahead of print on June 26, 2008, doi:10.1164/rccm.200801-061OC
© 2008 American Thoracic Society doi: 10.1164/rccm.200801-061OC
Airway Lipoxin A4 Generation and Lipoxin A4 Receptor Expression Are Decreased in Severe Asthma1 Pulmonary and Critical Care Medicine, and Partners Asthma Center, Department of Internal Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; 2 Pulmonary and Critical Care Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina; 3 Department of Preventive Medicine and Biometrics, National Jewish Medical and Research Center, Denver, Colorado; 4 Department of Pathobiology, Cleveland Clinic Foundation, Cleveland, Ohio; 5 Division of Allergy, Pulmonary, Immunology, Critical Care, and Sleep, University of Texas Medical Branch, Galveston, Texas; 6 Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri; 7 Department of Thoracic Medicine, Imperial College and Royal Brompton Hospital, London, United Kingdom; 8 Department of Pediatrics, University of Virginia Health Sciences Center, Charlottesville, Virginia; 9 Department of Medicine, Pulmonary and Critical Care Medicine, University of Wisconsin Medical Center, Madison, Wisconsin; and 10 Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania Correspondence and requests for reprints should be addressed to Bruce D. Levy, M.D., Pulmonary and Critical Care Medicine Division, Department of Internal Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115. E-mail: blevy{at}partners.org Rationale: Airway inflammation is common in severe asthma despite antiinflammatory therapy with corticosteroids. Lipoxin A4 (LXA4) is an arachidonic acid–derived mediator that serves as an agonist for resolution of inflammation. Objectives: Airway levels of LXA4, as well as the expression of lipoxin biosynthetic genes and receptors, in severe asthma. Methods: Samples of bronchoalveolar lavage fluid were obtained from subjects with asthma and levels of LXA4 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 LXA4 receptors were monitored by flow cytometry. Measurements and Main Results: Individuals with severe asthma had significantly less LXA4 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, LXA4 receptor gene and protein expression were significantly decreased in severe asthma peripheral blood granulocytes. Conclusions: 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.
Key Words: severe asthma • lipoxins • eicosanoids
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