title: Sphingosine-1-phosphate modulates vascular permeability and cell recruitment in acute inflammation in vivo.
abstract: The sphingosine kinase (SPK)/sphingosine-1-phosphate (S1P) pathway recently has been associated with a variety of inflammatory-based diseases. The majority of these studies have been performed in vitro. Here, we have addressed the relevance of the SPK/S1P pathway in the acute inflammatory response in vivo by using different well known preclinical animal models. The study has been performed by operating a pharmacological modulation using 1) L-cycloserine and DL-threo-dihydrosphingosine (DTD), S1P synthesis inhibitors or 2) 2-undecyl-thiazolidine-4-carboxylic acid (BML-241) and N-(2,6-dichloro-4-pyridinyl)-2-[1,3-dimethyl-4-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-hydrazinecarboxamide (JTE-013), specific S1P(2) and S1P(3) receptor antagonists. After local injection of carrageenan in mouse paw S1P release significantly increases locally and decreases during the resolution phase. Expression of SPKs and S1P(2) and S1P(3) receptors is increased in inflamed tissues. Administration of L-cycloserine or DTD caused a significant anti-inflammatory effect. By using different animal models we have also demonstrated that the SPK/S1P pathway contributes to changes in vascular permeability and promotes cell recruitment. The S1P effect on cell recruitment results is receptor-mediated because both JTE-013 and BML-241 inhibited zymosan-induced cell chemotaxis without effect on vascular leakage. Conversely, changes in vascular permeability involve mainly SPK activity, because compound 48/80-induced vascular leakage was significantly inhibited by DTD. In conclusion, the SPK/S1P pathway is involved in acute inflammation and could represent a valuable therapeutic target for developing a new class of anti-inflammatory drugs.
authors.affiliation: Dipartimento di Farmacologia Sperimentale, Università di Napoli Federico II, Domenico Montesano 49, 80131 Naples, Italy.
authors.forename: Fiorentina
authors.initials: F
authors.lastname: Roviezzo
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Brancaleone
authors.forename: Luana
authors.initials: L
authors.lastname: De Gruttola
authors.forename: Valentina
authors.initials: V
authors.lastname: Vellecco
authors.forename: Mariarosaria
authors.initials: M
authors.lastname: Bucci
authors.forename: Bruno
authors.initials: B
authors.lastname: D'Agostino
authors.forename: Dianne
authors.initials: D
authors.lastname: Cooper
authors.forename: Raffaella
authors.initials: R
authors.lastname: Sorrentino
authors.forename: Mauro
authors.initials: M
authors.lastname: Perretti
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cirino
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003523:Cycloserine / Q000494:pharmacology; D004487:Edema / Q000517:prevention & control; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D008246:Lysophospholipids / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D051379:Mice; D058990:Molecular Targeted Therapy; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D011720:Pyrazoles / Q000378:metabolism / Q000494:pharmacology; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D053778:Thiazolidines / Q000378:metabolism / Q000494:pharmacology; D000099157:Sphingosine Kinase
chemical_list: D003523:Cycloserine; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D011720:Pyrazoles; D011725:Pyridines; D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D053778:Thiazolidines; D000099157:Sphingosine Kinase; C515031:BML 241; C471998:JTE 013; C060506:sphingosine 1-phosphate; C005682:safingol