Montelukast regulates eosinophil protease activity through a leukotriene-independent mechanism - 17/08/11
Reprint requests: Michel Laviolette, MD, Hôpital Laval, 2725 Chemin Sainte-Foy, Quebec G1V 4G5, Canada.Sainte-Foy, Quebec, Canada
Abstract |
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) 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.
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.
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.
El texto completo de este artículo está disponible en PDF.Key words : Asthma, eosinophil, leukotrienes, matrix metalloproteinase 9, migration, montelukast, MK-0591, plasminogen activator inhibitor, urokinase plasminogen activator, urokinase plasminogen activator receptor
Abbreviations used : CysLT, CysLT1R, FLAP, LT, MMP, mOD, 5-oxo-ETE, PAI, uPA, uPAR, Vmax
Esquema
| Supported by the Canadian Institutes of Health Research (MOP-49534) and by Merck Frosst Canada Ltd. Disclosure of potential conflict of interest: M. Laviolette has received grants from Merck Frosst and is on the speakers’ bureau for 3M, GlaxoSmithKline, and AstraZeneca. G. Tremblay has received grants from Merck Frosst. The rest of the authors have declared that they have no conflict of interest. |
Vol 118 - N° 1
P. 113-119 - juillet 2006 Regresar al número
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