期刊
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
卷 118, 期 1, 页码 113-119出版社
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2006.03.010
关键词
asthma; eosinophil; leukotrienes; matrix metalloproteinase 9; migration; montelukast; MK-0591; plasminogen activator inhibitor; urokinase plasminogen activator; urokinase plasminogen activator receptor
Background: Migration of eosinophils into bronchial mucosa requires proteolysis. Montelukast, a cysteinyl leukotriene (CysLT) 1 receptor antagonist used in asthma treatment, decreases eosinophil infiltration into the asthmatic airways, suggesting that CysLTs modulate eosinophil protease activity. Objective: We sought to determine whether CysLTs and montelukast regulate eosinophil protease activity. Methods: Purified blood eosinophils were treated with or without montelukast; MK-0591, a 5-lipoxygenase-activating protein inhibitor; or leukotriene (LT) D-4. Migration assays through Matrigel were performed in the presence of 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE), a potent eosinophil chemotactic factor, or LTD4. Expression of molecules implicated in plasmin generation and matrix metalloproteinase (MMP) 9 release were also evaluated. Results: Montelukast and MK-0591 decreased eosinophil migration promoted by 5-oxo-ETE, whereas LTD4 failed to induce eosinophil migration. However, LTD4 significantly boosted the migration rate obtained with a suboptimal concentration of 5-oxo-ETE and partially reversed the inhibition obtained with MK-0591. Montelukast significantly reduced the maximal rate of activation of plasminogen into plasmin by eosinophils obtained with 5-oxo-ETE. 5-Oxo-ETE increased the number of eosinophils expressing urokinase plasminogen activator receptor and stimulated secretion of MMP-9. Montelukast, but neither MK-0591 nor LTD4, reduced the expression of urokinase plasminogen activator receptor and the secretion of MMP-9 and increased total cellular activity of urokinase plasminogen activator and the expression of plasminogen activator inhibitor 2 mRNA. C onclusion: Montelukast inhibits eosinophil protease activity in vitro through a mechanism that might be independent of its antagonist effect on CysLT 1 receptor. Clinical implications: This could partially explain montelukast's anti-inflammatory effect in asthma and eventually amplify to improve its therapeutic efficacy.
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