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A small molecule, orally active, α 4 β 1 / α 4 β 7 dual antagonist reduces leukocyte infiltration and airway hyper‐responsiveness in an experimental model of allergic asthma in Brown Norway rats
Author(s) -
Cortijo Julio,
Sanz MaríaJesús,
Iranzo Arantxa,
Montesinos José Luis,
Nabah Yafa Naim Abu,
Alfón José,
Gómez Luis A,
Merlos Manuel,
Morcillo Esteban J
Publication year - 2006
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0706658
Subject(s) - eosinophil , bronchoalveolar lavage , intravital microscopy , cell adhesion molecule , lymphocyte function associated antigen 1 , immunology , chemistry , integrin , medicine , endocrinology , intercellular adhesion molecule 1 , lung , microcirculation , receptor , asthma
α 4 β 1 and α 4 β 7 integrins are preferentially expressed on eosinophils and mononuclear leukocytes and play critical roles in their recruitment to inflammatory sites. We investigated the effects of TR14035, a small molecule, α 4 β 1 / α 4 β 7 dual antagonist, in a rat model of allergic asthma. Actively sensitized rats were challenged with aerosol antigen or saline on day 21, and the responses evaluated 24 and 48‐h later. TR14035 (3 mg kg −1 , p.o.) was given 1‐h before and 4‐h after antigen or saline challenge. Airway hyper‐responsiveness to intravenous 5‐hydroxytryptamine was suppressed in TR14035‐treated rats. Eosinophil, mononuclear cell and neutrophil counts, and eosinophil peroxidase and protein content in the bronchoalveolar lavage fluid (BALF) were decreased in TR14035‐treated rats. Histological study showed a marked reduction of lung inflammatory lesions by TR14035. At 24‐h postchallenge, antigen‐induced lung interleukin (IL)‐5 mRNA upregulation was suppressed in TR14035‐treated rats. By contrast, IL‐4 levels in BALF were not significantly affected by TR14035 treatment. IL‐4 selectively upregulates vascular cell adhesion molecule‐1 (VCAM‐1), which is the main endothelial ligand of α 4 integrins. Intravital microscopy within the rat mesenteric microcirculation showed that 24‐h exposure to 1 μ g per rat of IL‐4 induced a significant increase in leukocyte rolling flux, adhesion and emigration. These responses were decreased by 48, 100 and 99%, respectively in animals treated with TR14035. In conclusion, TR14035, by acting on α 4 β 1 and α 4 β 7 integrins, is an orally active inhibitor of airway leukocyte recruitment and hyper‐responsiveness in animal models with potential interest for the treatment of asthma.British Journal of Pharmacology (2006) 147 , 661–670. doi: 10.1038/sj.bjp.0706658