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Montelukast inhibition of resting and GM‐CSF‐stimulated eosinophil adhesion to VCAM‐1 under flow conditions appears independent of cysLT 1 R antagonism
Author(s) -
Robinson Alexander J.,
Kashanin Dmitry,
O'Dowd Frank,
Williams Vivienne,
Walsh Garry M.
Publication year - 2008
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.1007717
Subject(s) - eosinophil , biology , leukotriene , microbiology and biotechnology , adhesion , leukotriene d4 , pharmacology , chemistry , endocrinology , medicine , biochemistry , receptor , antagonist , immunology , organic chemistry , asthma
Montelukast (MLK) is a cysteinyl leukotriene receptor‐1 (cysLT 1 R) 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 LTC 4 , 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 LTC 4 did not enhance eosinophil adhesion. In contrast, LTD 4 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 cysLT 1 R antagonism.