Novel therapies are needed to'address the vascular endothelial cell (EC) barrier disruption which occurs in the context of inflammatory diseases such as acute lung injury (ALI). We have previously demonstrated the potent barrier-enhancing effects of both sphingosine 1-phosphate (SIP) and a structurally similar compound, FTY720 (FTY), in models of ALI. Despite its impressive potential, S1P is an endogenous compound that produces a myriad of potentially harmful effects which will limit its usefulness in patients. Therefore we have focused on FTY, which is currently being evaluated in Phase III clinical trials for other indications and may soon be a potential therapeutic option for ALI. Our prior studies demonstrate that FTY potently enhances EC barrier function through a novel and poorly understood mechanistic pathway that differs from SIP. However, FTY has immunosuppressive properties that may limit its therapeutic utility in patients with ALI. As a result, we have generated novel analogues of FTY to mechanistically explore these barrier-regulatory pathways and to identify more optimal therapeutic compounds. Our exciting preliminary data indicate that the FTY720 (S)-phosphonate (fTyS) analogue has superior efficacy in ALI models and maintains SIPRI receptor levels unlike other agonists which induce its ubiquitination and degradation. With this background, we propose the following specific aims. SA #1 will rigorously characterize the differential effects of the promising fTyS analogue in comparison with FTY and SIP on SIPRI expression, activation, ubiquitination, and degradation in vitro. SA #2 will mechanistically characterize in vitro fTyS in comparison with FTY and SIP for their relative effects on multiple aspects of EC barrier function in vitro, including intracellular signaling and junctional complex formation. SA #3 will extend these studies in vivo by defining pharmacologic properties of fTyS in mice and characterizing its effects on SIPRI expression and function in vivo. The relative effectiveness of fTyS, SIP, and FTY to attenuate lung injury will be compared in both short term (LPS) and long term (bleomycin) mouse ALI models to assess the potential use of these agents for prolonged therapy. We expect these studies to facilitate the development of targeted therapies to reduce vascular leak in ALI.

Public Health Relevance

The Acute Lung Injury/Acute Respiratory Distress Syndrome (ALI/ARDS) is a devastating consequence of systemic inflammatory conditions (such as sepsis) that afflicts an estimated 200,000 people a year in the US with 75,000 deaths. No specific therapy is available to target the underlying mechanistic causes of this syndrome. This proposal seeks to evaluate the potential therapeutic effectiveness of novel FTY720 analogues in models of this disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL098050-02
Application #
8375549
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
2
Fiscal Year
2012
Total Cost
$414,287
Indirect Cost
$120,841
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