TY - JOUR T1 - Selective Inhibition of Eosinophil Influx into the Lung by Small Molecule CC Chemokine Receptor 3 Antagonists in Mouse Models of Allergic Inflammation JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 411 LP - 417 DO - 10.1124/jpet.105.099812 VL - 318 IS - 1 AU - Anuk M. Das AU - Krishna G. Vaddi AU - Kimberly A. Solomon AU - Candice Krauthauser AU - Xiaosui Jiang AU - Kim W. McIntyre AU - Xiao Xia Yang AU - Eric Wadman AU - Patricia Welch AU - Maryanne Covington AU - Danielle Graden AU - Krishnaswamy Yeleswaram AU - James M. Trzaskos AU - Robert C. Newton AU - Sandhya Mandlekar AU - Soo S. Ko AU - Percy H. Carter AU - Paul Davies Y1 - 2006/07/01 UR - http://jpet.aspetjournals.org/content/318/1/411.abstract N2 - CC chemokine receptor (CCR) 3 is a chemokine receptor implicated in recruiting cells, particularly eosinophils (EΦ), 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 EΦ 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 EΦ was concentration- and time-dependent. Although anti-CCR3 antibody reduced the number of EΦ, 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 EΦ 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 equivalent to the in vitro chemotaxis IC90 but only at much higher concentrations. To extend the results from our recruitment model, we tested one of the inhibitors in an allergenic model of airway inflammation, generated by adoptive transfer of OVA-sensitive murine T helper 2 cells and aerosolized OVA challenge of recipient mice, and found that it inhibited EΦ recruitment. We conclude that small molecule CCR3 antagonists reduce pulmonary eosinophilic inflammation elicited by chemokine or allergenic challenge. The American Society for Pharmacology and Experimental Therapeutics ER -