| Title | Airway LXA4 Generation and LXA4 Receptor Expression are Decreased in Severe Asthma. | | Author(s) | Planaguma A, Kazani S, Marigowda G, Haworth O, Mariani TJ, Israel E, Bleecker ER, Curran-Everett D, Erzurum SC, Calhoun WJ, Castro M, Chung KF, Gaston B, Jarjour NN, Busse WW, Wenzel SE, Levy BD | | Institution | Pulmonary and Critical Care Medicine, and Partners Asthma Center, Department of Internal Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. | | Source | Am J Respir Crit Care Med 2008 Jun 26. | | Abstract | OBJECTIVES: Lipoxin A4 is an arachidonic acid-derived mediator that serves as an agonist for resolution of inflammation. Here, we determined airway levels of lipoxin A4, as well as the expression of lipoxin biosynthetic genes and receptors in severe asthma.
METHODS: Samples of bronchoalveolar lavage fluid were obtained from asthmatic subjects and levels of lipoxin A4 and related eicosanoids were measured. Expression of lipoxin biosynthetic genes was determined in whole blood, bronchoalveolar lavage cells, and endobronchial biopsies by quantitative PCR, and leukocyte lipoxin A4 receptors were monitored by flow cytometry.
RESULTS: Individuals with severe asthma had significantly less lipoxin A4 in bronchoalveolar lavage fluids (11.2 +/- 2.1 pg/ml) than subjects with not severe asthma (150.1 +/- 38.5 pg/ml, p <0.05). In contrast, levels of cysteinyl leukotrienes were increased in both asthma cohorts compared to healthy individuals. In severe asthma, 15-lipoxygenase-1 mean expression was decreased 5-fold in bronchoalveolar lavage cells. In contrast, 15-lipoxgenase-1 was increased 3-fold 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, lipoxin A4 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 counter-regulatory signaling circuits. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 18583575 |
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