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Published on: June 7, 2018
Montelukast regulates eosinophil protease activity through a leukotriene-independent mechanism
Anick Langlois1, Claudine Ferland, Guy M Tremblay
1Unité de Recherche en Pneumologie, Centre de Recherche de l'Hôpital Laval, Institut Universitaire de Cardiologie et de Pneumologie de l'Université Laval, 2725 Chemin Sainte-Foy, Quebec G1V 4G5, Canada.
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 LTD(4). 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 LTD(4) failed to induce eosinophil migration. However, LTD(4) 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 LTD(4), 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.
Conclusion:
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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