The devastating mortality associate with acute lung injury (ALI) is intimately related to profound vascular permeability and alveolar flooding with effectible therapy not currentiy available. Project 2 investigators were the first to demonstrate that the multifunctional lipid mediator, sphingosine 1-phosphate (SIP) potently enhances endothelial cell (EC) monolayer integrity and reduces vascular permeability via ligation of the G potein-coupled SIP receptor, S1PR1. We subsequently showed that S1PR1 ligation induces Rac GTPase signaling to the EC cytoskeleton and reduces LPS, ischemia/reperfusion, ventilator and radiation-induced increases in lung vascular permeability. S1PR1 is also critical to hepatocyte growth factor and activated protein C-mediated barrier enhancement via S1PR1 transactivation. In contrast, ligation of a related SIP receptor, S1PR3, induced Rho GTPase signaling, disrupts cell-cell junctions and increases lung permeability and alveolar flooding. These conflicting roles for specific SIPRs potentially limit utilization of SI Pas a therapeutic strategy for vascular barrier dysfunction in inflammatory lung syndromes. Project 2 will integrate translational SI P-S1 PR insights into strategies which limit ALI pathobiology. SA #1 will assess the dose and delivery route-dependent (intratracheal vs intravenous) effects of SIP and selective S1PR1 &S1PR3 agonists/antagonists on vascular leakage in genetically-engineered mice (S1P1+/-, S1P3-/-) in murine ALL SA#2 will detail regulation of S1PR1, S1PR1 and S1PR3 gene promoter activities by inflammatory stimuli and extend preliminary data evaluating SI PR promoter SNP effects on luciferase promoter activity. SA #3 will assess potential novel biomarkers in ALI focusing on levels of circulating SIP, S1PR3 shed from the EC surface and SIP pathway-related gene expression signatures. Finally, SA #4 will conduct association studies in Caucasian and African ALI cohorts to further link novel SNPs in SI P-related target genes to ALI susceptibility. In summary, Project #2 will clarify the key roles of SIP receptors in ALI pathobiology, and facilitate development of pharmacogenomic assays and SI P-based therapies for the critically ill.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
1P01HL098050-01A1
Application #
8114294
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2011-06-01
Budget End
2012-05-31
Support Year
1
Fiscal Year
2011
Total Cost
$392,499
Indirect Cost
Name
University of Illinois at Chicago
Department
Type
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Rizzo, Alicia N; Dudek, Steven M (2017) Endothelial Glycocalyx Repair: Building a Wall to Protect the Lung during Sepsis. Am J Respir Cell Mol Biol 56:687-688
Natarajan, Viswanathan; Ha, Alison W; Dong, Yangbasai et al. (2017) Expression profiling of genes regulated by sphingosine kinase1 signaling in a murine model of hyperoxia induced neonatal bronchopulmonary dysplasia. BMC Genomics 18:664
Huang, Long Shuang; Jiang, Peiyue; Feghali-Bostwick, Carol et al. (2017) Lysocardiolipin acyltransferase regulates TGF-? mediated lung fibroblast differentiation. Free Radic Biol Med 112:162-173
Ebenezer, David L; Fu, Panfeng; Suryadevara, Vidyani et al. (2017) Epigenetic regulation of pro-inflammatory cytokine secretion by sphingosine 1-phosphate (S1P) in acute lung injury: Role of S1P lyase. Adv Biol Regul 63:156-166
Sysol, Justin R; Natarajan, Viswanathan; Machado, Roberto F (2016) PDGF induces SphK1 expression via Egr-1 to promote pulmonary artery smooth muscle cell proliferation. Am J Physiol Cell Physiol 310:C983-92
Camp, Sara M; Chiang, Eddie T; Sun, Chaode et al. (2016) ""Pulmonary Endothelial Cell Barrier Enhancement by Novel FTY720 Analogs: Methoxy-FTY720, Fluoro-FTY720, and ?-Glucuronide-FTY720"". Chem Phys Lipids 194:85-93
Harijith, Anantha; Pendyala, Srikanth; Ebenezer, David L et al. (2016) Hyperoxia-induced p47phox activation and ROS generation is mediated through S1P transporter Spns2, and S1P/S1P1&2 signaling axis in lung endothelium. Am J Physiol Lung Cell Mol Physiol 311:L337-51
Fu, Panfeng; Ebenezer, David L; Berdyshev, Evgeny V et al. (2016) Role of Sphingosine Kinase 1 and S1P Transporter Spns2 in HGF-mediated Lamellipodia Formation in Lung Endothelium. J Biol Chem 291:27187-27203
Jiang, Ying; Sverdlov, Maria S; Toth, Peter T et al. (2016) Phosphatidic Acid Produced by RalA-activated PLD2 Stimulates Caveolae-mediated Endocytosis and Trafficking in Endothelial Cells. J Biol Chem 291:20729-38
Ebenezer, David L; Fu, Panfeng; Natarajan, Viswanathan (2016) Targeting sphingosine-1-phosphate signaling in lung diseases. Pharmacol Ther 168:143-157

Showing the most recent 10 out of 60 publications