title: Sphingosine-1-phosphate/sphingosine kinase pathway is involved in mouse airway hyperresponsiveness.
abstract: Sphingosine-1-phosphate (S1P) has been shown to regulate numerous and diverse cell functions, including smooth muscle contraction. Here we assessed the role of S1P/Sphingosine kinase (SPK) pathway in the regulation of bronchial tone. Our objective was to determine, using an integrated pharmacologic and molecular approach, (1) the role of S1P as endogenous modulator of the bronchial tone, and (2) the linkage between S1P pathway and bronchial hyperresponsiveness. We evaluated S1P effects on isolated bronchi and whole lungs, harvested from Balb/c mice sensitized to ovalbumin (OVA) versus vehicle-treated mice, by measuring bronchial reactivity and lung resistance. We found that S1P administration on nonsensitized mouse bronchi does not cause any direct effect on bronchial tone, while a significant increase in Ach-induced contraction occurs after S1P challenge. Conversely, in OVA-sensitized mice S1P/SPK pathway triggers airway hyperesponsiveness. Indeed, S1P causes a dose-dependent contraction of isolated bronchi. Similarly, in the whole lung system S1P increased airway resistance only in OVA-sensitized mice. The action on bronchi of S1P is coupled to an enhanced expression of SPK(1) and SPK(2) as well as of S1P(2) and S1P(3) receptors. In these experiments the key role for S1P/SPK in hyperreactivity has been confirmed by pharmacologic modulation of SPKs. S1P/SPK pathway does not seem to play a major role in physiologic conditions, while it may become critical in pathologic conditions. These results open new windows for therapeutic strategies in diseases like asthma.
authors.affiliation: Dipartimento di Farmacologia Sperimentale, Università di Napoli Federico II, Napoli, Italy.
authors.forename: Fiorentina
authors.initials: F
authors.lastname: Roviezzo
authors.forename: Annarita
authors.initials: A
authors.lastname: Di Lorenzo
authors.forename: Mariarosaria
authors.initials: M
authors.lastname: Bucci
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Brancaleone
authors.forename: Valentina
authors.initials: V
authors.lastname: Vellecco
authors.forename: Marilisa
authors.initials: M
authors.lastname: De Nardo
authors.forename: Donatella
authors.initials: D
authors.lastname: Orlotti
authors.forename: Raffaele
authors.initials: R
authors.lastname: De Palma
authors.forename: Francesco
authors.initials: F
authors.lastname: Rossi
authors.forename: Bruno
authors.initials: B
authors.lastname: D'Agostino
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cirino
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001980:Bronchi / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D016535:Bronchial Hyperreactivity / Q000378:metabolism*; D018678:Cholinergic Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008246:Lysophospholipids / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009129:Muscle Tonus; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D010047:Ovalbumin / Q000276:immunology / Q000494:pharmacology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D000109:Acetylcholine; D018678:Cholinergic Agents; D008246:Lysophospholipids; D010047:Ovalbumin; D017853:Phosphotransferases (Alcohol Group Acceptor); D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate