Airway lipoxin A4 generation and lipoxin A4 receptor expression are decreased in severe asthma

Anna Planagumà, Shamsah Kazani, Gautham Marigowda, Oliver Haworth, Thomas J. Mariani, Elliot Israel, Eugene R. Bleecker, Douglas Curran-Everett, Serpil C. Erzurum, William J. Calhoun, Mario Castro, Fan Chung Kian, Benjamin Gaston, Nizar N. Jarjour, William W. Busse, Sally E. Wenzel, Bruce D. Levy

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163 Scopus citations

Abstract

Rationale: Airway inflammation is common in severe asthma despite antiinflammatory therapy with corticosteroids. Lipoxin A4 (LXA 4) 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 enzymesand receptors. Together, these results indicate that severe asthma is characterized, in part, by defective lipoxin counterregulatory signaling circuits.

Original languageEnglish
Pages (from-to)574-582
Number of pages9
JournalAmerican journal of respiratory and critical care medicine
Volume178
Issue number6
DOIs
StatePublished - Sep 15 2008

Keywords

  • Eicosanoids
  • Lipoxins
  • Severe asthma

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    Planagumà, A., Kazani, S., Marigowda, G., Haworth, O., Mariani, T. J., Israel, E., Bleecker, E. R., Curran-Everett, D., Erzurum, S. C., Calhoun, W. J., Castro, M., Kian, F. C., Gaston, B., Jarjour, N. N., Busse, W. W., Wenzel, S. E., & Levy, B. D. (2008). Airway lipoxin A4 generation and lipoxin A4 receptor expression are decreased in severe asthma. American journal of respiratory and critical care medicine, 178(6), 574-582. https://doi.org/10.1164/rccm.200801-061OC