Received for publication December 22, 2005.
Revised April 11, 2006.
Accepted for publication April 11, 2006.

Selective inhibition of eosinophil influx into the lung by small molecule CCR3 antagonists in mouse models of allergic inflammation

Abstract

CCR3 is a chemokine receptor implicated in recruiting cells, particularly eosinophils, 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 eosinophil recruitment to the lung. Murine eotaxin was delivered intra-nasally to mice that had previously received intra-peritoneal injections of ovalbumin, and the effects were monitored by broncho-alveolar lavage. A selective eosinophilic influx was produced in animals receiving eotaxin but not saline. Furthermore, the number of eosinophils was concentration- and time-dependent. Although anti-CCR3 antibody reduced the number of eosinophils, the effect of eotaxin in ovalbumin-sensitized mice was not a direct chemotactic stimulus since mast cell deficiency (in W/W^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 orally to wild-type mice and found to reduce eotaxin-elicited eosinophils 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. In order 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 ovalbumin-sensitive murine Th₂-cells and aerosolized ovalbumin challenge of recipient mice, and found that it inhibited eosinophil recruitment. We conclude that small molecule CCR3 antagonists reduce pulmonary eosinophilic inflammation elicited by chemokine or allergenic challenge.

Key words: airway, asthma, chemokine, eotaxin, mast cell, pulmonary

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