Montelukast regulates eosinophil protease activity through a leukotriene-independent mechanism

BackgroundMigration 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.ObjectiveWe sought to determine whether CysLTs and montelukast regulate eosinophil protease activity.MethodsPurified blood eosinophils were treated with or without montelukast; MK-0591, a 5-lipoxygenase–activating protein inhibitor; or leukotriene (LT) D4. 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.ResultsMontelukast 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.ConclusionMontelukast inhibits eosinophil protease activity in vitro through a mechanism that might be independent of its antagonist effect on CysLT 1 receptor.Clinical implicationsThis could partially explain montelukast's anti-inflammatory effect in asthma and eventually amplify to improve its therapeutic efficacy.