FTY720 (s)-phosphonate preserves sphingosine 1-phosphate receptor 1 expression and exhibits superior barrier protection to FTY720 in acute lung injury.

TitleFTY720 (s)-phosphonate preserves sphingosine 1-phosphate receptor 1 expression and exhibits superior barrier protection to FTY720 in acute lung injury.
Publication TypeJournal Article
Year of Publication2014
AuthorsWang L, Sammani S, Moreno-Vinasco L, Letsiou E, Wang T, Camp SM, Bittman R, Garcia JGN, Dudek SM
JournalCrit Care Med
Volume42
Issue3
Paginatione189-99
Date Published2014 Mar
ISSN Number1530-0293
KeywordsAcute Lung Injury, Animals, Arrestins, beta-Arrestins, Bleomycin, Blotting, Western, Capillary Permeability, Cells, Cultured, Disease Models, Animal, Endothelial Cells, Fingolimod Hydrochloride, Fluorescent Antibody Technique, Humans, Mice, Mice, Inbred C57BL, Propylene Glycols, Random Allocation, Receptors, G-Protein-Coupled, Receptors, Lysosphingolipid, Sensitivity and Specificity, Sphingosine
Abstract

<p><b>OBJECTIVE: </b>Effective therapies are needed to reverse the increased vascular permeability that characterizes acute inflammatory diseases such as acute lung injury. FTY720 is a pharmaceutical analog of the potent barrier-enhancing phospholipid, sphingosine 1-phosphate. Because both FTY720 and sphingosine 1-phosphate have properties that may limit their usefulness in patients with acute lung injury, alternative compounds are needed for therapeutic use. The objective of this study is to characterize the effects of FTY720 (S)-phosphonate, a novel analog of FTY720-phosphate, on variables of pulmonary vascular permeability in vitro and alveolar-capillary permeability in vivo.</p><p><b>SETTING: </b>University-affiliated research institute.</p><p><b>SUBJECTS: </b>Cultured human pulmonary endothelial cells; C57BL/6 mice.</p><p><b>INTERVENTIONS: </b>Endothelial cells were stimulated with sphingosine 1-phosphate receptor 1 agonists to determine effects on sphingosine 1-phosphate receptor 1 expression. Acute lung injury was induced in C57BL/6 mice with bleomycin to assess effects of sphingosine 1-phosphate receptor 1 agonists.</p><p><b>MEASUREMENTS AND MAIN RESULTS: </b>FTY720 (S)-phosphonate potently increases human pulmonary endothelial cell barrier function in vitro as measured by transendothelial electrical resistance. Reduction of sphingosine 1-phosphate receptor 1 with small interference RNA significantly attenuates this transendothelial electrical resistance elevation. FTY720 (S)-phosphonate maintains endothelial sphingosine 1-phosphate receptor 1 protein expression in contrast to greater than 50% reduction after incubation with sphingosine 1-phosphate, FTY720, or other sphingosine 1-phosphate receptor 1 agonists. FTY720 (S)-phosphonate does not induce β-arrestin recruitment, sphingosine 1-phosphate receptor 1 ubiquitination, and proteosomal degradation that occur after other agonists. Intraperitoneal administration of FTY720 (S)-phosphonate every other day for 1 week in normal or bleomycin-injured mice maintains significantly higher lung sphingosine 1-phosphate receptor 1 expression compared with FTY720. FTY720 fails to protect against bleomycin-induced acute lung injury in mice, while FTY720 (S)-phosphonate significantly decreases lung leak and inflammation.</p><p><b>CONCLUSION: </b>FTY720 (S)-phosphonate is a promising barrier-promoting agent that effectively maintains sphingosine 1-phosphate receptor 1 levels and improves outcomes in the bleomycin model of acute lung injury.</p>

DOI10.1097/CCM.0000000000000097
Alternate JournalCrit. Care Med.
PubMed ID24335440
PubMed Central IDPMC4144721
Grant ListR01 HL 88144 / HL / NHLBI NIH HHS / United States
P01 HL 58064 / HL / NHLBI NIH HHS / United States
P01 HL 98050 / HL / NHLBI NIH HHS / United States
P01 HL098050 / HL / NHLBI NIH HHS / United States
R01 HL088144 / HL / NHLBI NIH HHS / United States
P01 HL058064 / HL / NHLBI NIH HHS / United States