Sphingosine-1-phosphate induced airway hyperreactivity in rodents is mediated by the S1P3 receptor

There is a need to better understand the mechanism of airway hyperreactivity, a key feature of asthma. Evidence suggests that sphingosine-1-phosphate (S1P) could be a major player in this phenomenon. The purpose of this work was to define the S1P receptor responsible for this phenomenon. We have studied, in the rat, the effect of two S1P synthetic receptor ligands, FTY720 (which in its phosphorylated form is a potent agonist at each S1P receptor except S1P2) and AUY954 (a highly selective S1P1 agonist) on lung function in vivo. This was complemented by in vitro studies using isolated trachea from the rat, the S1P3 receptor-deficient mouse and its wild type counterpart. Following oral administration, FTY720 induced a generalized airway hyperreactivity to a range of contractile stimuli. This was observed as early as one hour post dosing, lasted for at least 24 hours and was not subject to desensitization. In both the rat and wild type mouse isolated trachea, pre-incubation with the active phosphorylated metabolite of FTY720, induced hyperresponsiveness to 5-HT. This effect was not seen in the isolated tracheas from S1P3 receptor-deficient mice. AUY954, did not mimic the effect of FTY720 either in vivo or in vitro. Our data are consistent with activation of the S1P pathway inducing a generalized airway hyperreactivity in rats and mice that is mediated by the S1P3 receptor. S1P3 receptor antagonists might prove useful as new therapeutic strategies aimed at blocking the airway hyperreactivity observed in asthma