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Published online before print March 10, 2008

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1007717

Received for publication October 29, 2007.
Revised January 30, 2008.
Accepted for publication February 6, 2008.

Article

Montelukast inhibition of resting and GM-CSF-stimulated eosinophil adhesion to VCAM-1 under flow conditions appears independent of cysLT₁R antagonism

Alexander J. Robinson ^*, Dmitry Kashanin , Frank O'Dowd , Vivienne Williams , and Garry M. Walsh ^*@

*School of Medicine, University of Aberdeen, Aberdeen, Scotland, United Kingdom; and Cellix Ltd., Institute of Molecular Medicine, St. James Hospital, Dublin, Ireland

^@ To whom correspondence should be addressed. E-mail: g.m.walsh{at}abdn.ac.uk.

	Abstract

Montelukast (MLK) is a cysteinyl leukotriene receptor-1 (cysLT₁R) antagonist with inhibitory effects on eosinophils, key proinflammatory cells in asthma. We assessed the effect of MLK on resting and GM-CSF-stimulated eosinophil adhesion to recombinant human (rh)VCAM-1 at different flow rates using our novel microflow system. At 1 or 2 dyn cm^–2, shear-stress unstimulated eosinophils tethered immediately to rhVCAM-1, "rolled" along part of the channel until they tethered, or rolled without tethering. At flow rates greater than 2 dyn cm^–2, adherent eosinophils began to be displaced from rhVCAM-1. MLK (10 nM and 100 nM) gave partial (40%) but significant (P<0.05) inhibition of unstimulated eosinophil adhesion to rhVCAM-1 at 1 or 2 dyn cm^–2 shear stress. Once adhered, unstimulated eosinophils did not exhibit morphological changes, and GM-CSF-stimulated eosinophil adhesion under flow was characterized by greater cell flattening with significant (P<0.05) inhibition of adherent cell numbers by 100 nM MLK observed. This effect appeared specific for MLK, as the analog (E)-3-[[[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-[[3-dimethylamino)-3-oxopropyl]thio]methyl]thio]-propanoic acid, sodium salt, had no significant effect on eosinophil adhesion to VCAM-1. The possibility that LTC₄, released from unstimulated or GM-CSF-treated eosinophils, contributed to their adhesion to VCAM-1 was excluded as the LT biosynthesis inhibitor 3-[1-(p-Chlorobenzyl)-5-(isopropyl)-3-t-butylthioindol-2-yl]-2,2-dimethylpropanoic acid had no inhibitory effect, and exogenously added LTC₄ did not enhance eosinophil adhesion. In contrast, LTD₄ enhanced eosinophil adhesion to VCAM-1, an effect blocked by MLK (10 and 100 nM). These findings demonstrate that MLK-mediated inhibition of unstimulated and GM-CSF-stimulated eosinophil adhesion to VCAM-1 under shear-stress conditions appears independent of cysLT₁R antagonism.

Key Words: asthma • migration • VLA-4