Sphingosine-1-Phosphate-Induced Airway Hyper-Reactivity in Rodents Is Mediated by the Sphingosine-1-Phosphate Type 3 Receptor

There is a need to better understand the mechanism of airway hyper-reactivity, 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, 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol (FTY720) (which in its phosphorylated form is a potent agonist at each S1P receptor except S1P(2)) and 3-[[2-[4-phenyl-3-(trifluoromethyl)phenyl]-1-benzothiophen-5-yl]methylamino]propanoic acid (AUY954) (a selective S1P(1) agonist) on lung function in vivo. This was complemented by in vitro studies using isolated trachea from the rat, the S1P(3) receptor-deficient mouse, and its wild-type counterpart. After oral administration, FTY720 induced a generalized airway hyper-reactivity to a range of contractile stimuli. This was observed as early as 1 h postdosing, lasted for at least 24 h, and was not subject to desensitization. In both rat and wild-type mouse isolated trachea, preincubation with the active phosphorylated metabolite of FTY720 induced hyper-responsiveness to 5-hydroxytryptamine. This effect was not seen in the isolated tracheas from S1P(3) 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 hyper-reactivity in rats and mice that is mediated by the S1P(3) receptor. S1P(3) receptor antagonists might prove to be useful as new therapeutic strategies aimed at blocking the airway hyper-reactivity observed in asthma.