Activation of the lung S1P(1) receptor reduces allergen-induced plasma leakage in mice.
OBJECTIVE
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.


METHODS
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 (S1P) receptor responsible for the anti-inflammatory effect of FTY720.


RESULTS
When given intranasally, FTY720 (3 and 10 microg.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 microg.kg(-1)). Similar results were observed in S1P(3)-deficient mice. The effect of FTY720 was mimicked by intranasal treatment of wild-type mice with a S1P(1)-specific agonist, AUY954.


CONCLUSIONS
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 lung, via activation of the S1P(1) receptor, is obtainable without systemic effects.
Blé
F-X
FX
Global Imaging Group, Novartis Institutes for BioMedical Research, Basel, Switzerland.
Cannet
C
C
Zurbruegg
S
S
Gérard
C
C
Frossard
N
N
Beckmann
N
N
Trifilieff
A
A
D000281:Administration, Intranasal; D000485:Allergens / Q000276:immunology*; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology*; D019819:Budesonide / Q000494:pharmacology; D002199:Capillary Permeability; D004305:Dose-Response Relationship, Drug; D005260:Female; D000068876:Fingolimod Hydrochloride; D007155:Immunologic Factors / Q000008:administration & dosage / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011014:Pneumonia / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D011409:Propylene Glycols / Q000008:administration & dosage / Q000494:pharmacology*; D011654:Pulmonary Edema / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000235:genetics; D013110:Sphingosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000081025:Sphingosine-1-Phosphate Receptors; D013876:Thiophenes / Q000494:pharmacology; D015091:beta-Alanine / Q000031:analogs & derivatives / Q000494:pharmacology
C517408:AUY 954; D000485:Allergens; D018927:Anti-Asthmatic Agents; D000893:Anti-Inflammatory Agents; D007155:Immunologic Factors; D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; C501285:S1pr3 protein, mouse; D000081025:Sphingosine-1-Phosphate Receptors; D013876:Thiophenes; D015091:beta-Alanine; D019819:Budesonide; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine