Selective inhibition of eosinophil influx into the lung by small molecule CC chemokine receptor 3 antagonists in mouse models of allergic inflammation

The Journal of Pharmacology and Experimental Therapeutics
Anuk M DasPaul Davies

Abstract

CC chemokine receptor (CCR) 3 is a chemokine receptor implicated in recruiting cells, particularly eosinophils (EPhi), to the lung in episodes of allergic asthma. To investigate the efficacy of selective, small molecule antagonists of CCR3, we developed a murine model of EPhi recruitment to the lung. Murine eotaxin was delivered intranasally to mice that had previously received i.p. injections of ovalbumin (OVA), and the effects were monitored by bronchoalveolar lavage. A selective eosinophilic influx was produced in animals receiving eotaxin but not saline. Furthermore, the number of EPhi was concentration- and time-dependent. Although anti-CCR3 antibody reduced the number of EPhi, the effect of eotaxin in OVA-sensitized mice was not a direct chemotactic stimulus because mast cell deficiency (in WBB6F1-Kitw/Kitw-v mice) significantly reduced the response. Two representative small molecule CCR3 antagonists from our program were characterized as being active at mouse CCR3. They were administered p.o. to wild-type mice and found to reduce eotaxin-elicited EPhi selectively in a dose-dependent manner. Pump infusion of one of the inhibitors to achieve steady-state levels showed that efficacy was not achieved at plasma concentrations...Continue Reading

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Citations

May 28, 2008·Expert Reviews in Molecular Medicine·Bennett O V ShumWilliam A Sewell
Apr 9, 2011·American Journal of Respiratory Cell and Molecular Biology·Michael Wegmann
Mar 5, 2008·Journal of Occupational Medicine and Toxicology·Gaetano CaramoriAlberto Papi
Jan 2, 2013·Frontiers in Bioscience (Scholar Edition)·Christine M Deppong, Jonathan M Green
Nov 28, 2015·Journal of Cellular and Molecular Medicine·Dong-Hyeon SuhYoo Seob Shin
Nov 28, 2012·Immunology Letters·Mehdi Houimel, Luca Mazzucchelli
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Feb 6, 2008·The Journal of Immunology : Official Journal of the American Association of Immunologists·Yung-Chang SuWilliam A Sewell

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