Montelukast regulates eosinophil protease activity through a leukotriene-independent mechanism.
J Allergy Clin Immunol
; 118(1): 113-9, 2006 Jul.
Article
em En
| MEDLINE
| ID: mdl-16815146
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) 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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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Quinolinas
/
Leucotrienos
/
Antagonistas de Leucotrienos
/
Cisteína
/
Eosinófilos
/
Acetatos
Limite:
Adult
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
J Allergy Clin Immunol
Ano de publicação:
2006
Tipo de documento:
Article
País de afiliação:
Canadá