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

Abstract

RATIONALE:

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.

OBJECTIVES:

Airway levels of LXA(4), 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 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.

MEASUREMENTS AND MAIN RESULTS:

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.

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.

• Authors: 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, Kian Fan Chung, Benjamin Gaston, Nizar N Jarjour, William W Busse, Sally E Wenzel, Bruce D Levy
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 178 Issue 6 Pg. 574-82 (Sep 15 2008) ISSN: 1535-4970 [Electronic] United States
• PMID: 18583575 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• FPR2 protein, human
• Hydroxyeicosatetraenoic Acids
• Lipoxins
• Receptors, Formyl Peptide
• Receptors, Lipoxin
• lipoxin A4
• 15-hydroxy-5,8,11,13-eicosatetraenoic acid

Topics

• Adult
• Asthma (blood, metabolism)
• Bronchi (metabolism)
• Bronchoalveolar Lavage Fluid (chemistry)
• Female
• Flow Cytometry
• Humans
• Hydroxyeicosatetraenoic Acids (blood)
• Lipoxins (biosynthesis, blood)
• Male
• Middle Aged
• Polymerase Chain Reaction
• Receptors, Formyl Peptide (metabolism)
• Receptors, Lipoxin (metabolism)