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

Abstract

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 hyperreactivity observed in asthma.

Exploration of the Sphingolipid Metabolite, Sphingosine-1-phosphate and Sphingosine, as Novel Biomarkers for Aspirin-exacerbated Respiratory Disease

“…In addition, IL-13 may induce release of periostin from bronchial epithelial cells32. S1P is known to be associated with airway hyperactivity and Th2 cytokines in mouse lung101133. S1P induction could lead to the release of Th2 cytokines, such as IL-4 and IL-131034.…”

Population of sensory neurons essential for asthmatic hyperreactivity of inflamed airways

“…4A); (ii) S1P levels are dramatically increased in ovalbuminsensitized lungs of mice (Fig. S6); and (iii) S1PR3 has been broadly implicated as a potential player in the development of asthma in humans and in rodent models of the disease (28)(29)(30). To assess the effect of S1PR3 activation on airway responses, we used a S1PR3 agonist (FTY720) (31) and tested airway mechanics.…”

Coadministration of FTY720 and rt-PA in an experimental model of large hemispheric stroke–no influence on functional outcome and blood–brain barrier disruption

“…Therefore, we have no information on whether the combination therapy led to an increase in hemorrhagic transformation. Concerning alternative extracranial causes of mortality, FTY720 has been shown to induce bradycardia [21], bronchoconstriction and mild pulmonary edema [22] in mice and humans. Besides that, the paucity of circulating lymphocytes could in principle entrain an increased susceptibility towards infections, even though we showed previously, that FTY720 does not increase the rate of stroke associated pneumonia in mice [23] and similar findings have been shown for equally specific immunomodulatory interventions in experimental stroke [24].…”