Montelukast regulates eosinophil protease activity through a leukotriene-independent mechanism.
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.


CONCLUSIONS
Montelukast inhibits eosinophil protease activity in vitro through a mechanism that might be independent of its antagonist effect on CysLT 1 receptor.


CONCLUSIONS
This could partially explain montelukast's anti-inflammatory effect in asthma and eventually amplify to improve its therapeutic efficacy.
Langlois
Anick
A
Unité 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.
Ferland
Claudine
C
Tremblay
Guy M
GM
Laviolette
Michel
M
D000085:Acetates / Q000494:pharmacology*; D000328:Adult; D001095:Arachidonic Acids / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D003521:Cyclopropanes; D003545:Cysteine / Q000502:physiology*; D004789:Enzyme Activation; D004804:Eosinophils / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D020024:Leukotriene Antagonists / Q000494:pharmacology*; D015289:Leukotrienes / Q000502:physiology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000032:analysis; D055293:Receptors, Urokinase Plasminogen Activator; D013440:Sulfides; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
D000085:Acetates; D001095:Arachidonic Acids; D003521:Cyclopropanes; D007211:Indoles; D020024:Leukotriene Antagonists; D015289:Leukotrienes; C524898:PLAUR protein, human; D011804:Quinolines; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D013440:Sulfides; C112381:cysteinyl-leukotriene; C080828:5-oxo-6,8,11,14-eicosatetraenoic acid; C078266:MK 0591; D014568:Urokinase-Type Plasminogen Activator; D020780:Matrix Metalloproteinase 9; D003545:Cysteine; C093875:montelukast