PT - JOURNAL ARTICLE AU - Fiorentina Roviezzo AU - Vincenzo Brancaleone AU - Luana De Gruttola AU - Valentina Vellecco AU - Mariarosaria Bucci AU - Bruno D'Agostino AU - Dianne Cooper AU - Raffaella Sorrentino AU - Mauro Perretti AU - Giuseppe Cirino TI - Sphingosine-1-Phosphate Modulates Vascular Permeability and Cell Recruitment in Acute Inflammation In Vivo AID - 10.1124/jpet.111.179168 DP - 2011 Jun 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 830--837 VI - 337 IP - 3 4099 - http://jpet.aspetjournals.org/content/337/3/830.short 4100 - http://jpet.aspetjournals.org/content/337/3/830.full SO - J Pharmacol Exp Ther2011 Jun 01; 337 AB - 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 S1P2 and S1P3 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 S1P2 and S1P3 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.