Activation of the lung S1P 1 receptor reduces allergen-induced plasma leakage in mice

Abstract

Background and purpose: It has been suggested that Intratracheal administration of the immunomodulator, FTY720, could have anti-inflammatory effects without causing a decrease In blood lymphocyte counts. However, the receptor responsible for this effect has not been defined. Experimental approach: We have described, In a mouse model of allergen-induced inflammation, the use of proton magnetic resonance imaging to non-invasively assess lung fluid accumulation and inflammation. Here, we used this model to investigate the sphingosine-1 -phosphate (SI P) receptor responsible for the anti-inflammatory effect of FTY720. Key results: When given intranasally, FTY720 (3 and 10μg.kg -1) inhibited by approximately 50% the allergen-induced accumulation of fluid in the lung detected by magnetic resonance imaging, but had no effect on the cellular inflammation in the airway space or on circulating blood lymphocytes. Inhibition of the infiltration of inflammatory cells into the airways was only observed at a dose of FTY720 that induced lymphopenia (100 (μg.kg -1). Similar results were observed in SI P 3-deficient mice. The effect of FTY720 was mimicked by intranasal treatment of wild-type mice with a SI P 1-specific agonist, AUY954. Conclusions and implications: Thus, in contrast to previously published work, our results suggest that systemic exposure of FTY720 is necessary to obtain an airway anti-inflammatory effect. On the contrary, inhibition of the allergen-induced accumulation of fluid In the lunq, via activation of the SI P 1 receptor, is obtainable without systemic effects. © 2009 The British Pharmacological Society All rights reserved.