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Airway Lipoxin A₄ Generation and Lipoxin A₄ Receptor Expression Are Decreased in Severe Asthma

¹ 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

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Lipoxins are potent antiinflammatory and proresolving mediators that are generated during inflammatory responses to promote catabasis. Lipoxin A4 (LXA4) biosynthetic capacity is decreased in whole blood in severe asthma. What This Study Adds to the Field In severe asthma, airway LXA4 levels and expression of lipoxin biosynthetic enzymes and receptors were markedly decreased. Thus, severe asthma is characterized in part by defective lipoxin counterregulatory signaling circuits.