Role of sphingosine-1-phosphate (S1P) and the S1P(2) receptor in allergen-induced, mast cell-dependent contraction of rat lung parenchymal strips.
Lung parenchymal strips isolated from ovalbumin-sensitized rats manifest a mast cell-dependent, biphasic contraction when challenged with allergen. The first phase is mediated by the release of preformed 5-HT while the second phase is dependent on de novo synthesis of leukotrienes. Sphingosine 1-phosphate (S1P) is a sphingolipid metabolite which is readily generated in mast cells and has been demonstrated to be an important regulator of allergen-induced mast cell activation. We have used the parenchymal strip to explore the role of sphingosine 1-phosphate and the S1P(2) receptor in the two components of the acute response to allergen. Lung parenchymal strips were prepared from Brown Norway rats actively sensitized to ovalbumin. The strips were set up in organ baths and contractile responses measured isometrically. The inhibitors of sphingosine kinase, D-erythro-NN-dimethylsphingosine (dimethylsphingosine) and 4-[4-(4-chloro-phenyl)-thiazol-2-ylamino]-phenol (SKI-II) inhibited concentration-dependently both phases of the contractile response induced by 0.1 microg ml(-1) ovalbumin. The effects were seen at concentrations similar to those which inhibit the purified enzyme and were selective in that neither the contractile response to adenosine nor that to 5-hydroxytryptamine was affected. JTE-013 (a selective S1P(2) receptor antagonist) also blocked the response to ovalbumin (0.1 microg ml(-1)). However, the concentrations of JTE-013 required (microM) were substantially higher than its affinity for the S1P(2) receptors (nM). However, when tested against a lower concentration of ovalbumin (0.03 microg ml(-1)), JTE-013 inhibited the response with nM potency. These data demonstrate the importance of S1P and the S1P(2) receptor as regulators of allergen-induced activation of mast cells in their natural environment in the rat lung.
Trifilieff
A
A
Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Novartis AG, 4002 Basel, Switzerland. alexandre.trifilieff@novartis.com
Baur
F
F
Fozard
J R
JR
D000085:Acetates / Q000494:pharmacology; D000241:Adenosine / Q000378:metabolism; D000485:Allergens / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects*; D003521:Cyclopropanes; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007279:Injections, Subcutaneous; D020024:Leukotriene Antagonists / Q000494:pharmacology; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism*; D008297:Male; D008407:Mast Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008784:Methysergide / Q000494:pharmacology; D010047:Ovalbumin / Q000008:administration & dosage / Q000494:pharmacology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D011914:Rats, Inbred BN; D049349:Receptors, Lysosphingolipid / Q000187:drug effects* / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D013440:Sulfides; D013844:Thiazoles / Q000494:pharmacology; D000099157:Sphingosine Kinase
D000085:Acetates; D000241:Adenosine; D000485:Allergens; D003521:Cyclopropanes; D004791:Enzyme Inhibitors; D020024:Leukotriene Antagonists; D008246:Lysophospholipids; D008784:Methysergide; D010047:Ovalbumin; D017853:Phosphotransferases (Alcohol Group Acceptor); D011720:Pyrazoles; D011725:Pyridines; D011804:Quinolines; D049349:Receptors, Lysosphingolipid; D012701:Serotonin; D012702:Serotonin Antagonists; D013110:Sphingosine; D013440:Sulfides; D013844:Thiazoles; D000099157:Sphingosine Kinase; C525025:4-(4-(4-chloro-phenyl)thiazol-2-ylamino)phenol; C471998:JTE 013; C060506:sphingosine 1-phosphate; C061800:N,N-dimethylsphingosine; C093875:montelukast