Synthetic analogs of FTY720 [2-amino-2-(2-[4-octylphenyl]ethyl)-1,3- propanediol] differentially regulate pulmonary vascular permeability in vivo and in vitro

S. M. Camp, R. Bittman, E. T. Chiang, L. Moreno-Vinasco, T. Mirzapoiazova, S. Sammani, X. Lu, C. Sun, M. Harbeck, M. Roe, V. Natarajan, Joe GN Garcia, Steven M. Dudek

Research output: Contribution to journalArticle

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Abstract

Novel therapies are needed to address the vascular endothelial cell (EC) barrier disruption that occurs in inflammatory diseases such as acute lung injury (ALI). We previously demonstrated the potent barrier-enhancing effects of both sphingosine 1-phosphate (S1P) and the structurally similar compound FTY720 [2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol] in inflammatory lung injury. In this study, we examined the therapeutic potential of several novel FTY720 analogs to reduce vascular leak. Similar to S1P and FTY720, the (R)- and (S)-enantiomers of FTY720 phosphonate and enephosphonate analogs produce sustained EC barrier enhancement in vitro, as seen by increases in transendothelial electrical resistance (TER). In contrast, the (R)- and (S)-enantiomers of FTY720-regioisomeric analogs disrupt EC barrier integrity in a dose-dependent manner. Barrier-enhancing FTY720 analogs demonstrate a wider protective concentration range in vitro (1-50 μM) and greater potency than either S1P or FTY720. In contrast to FTY720-induced EC barrier enhancement, S1P and the FTY720 analogs dramatically increase TER within minutes in association with cortical actin ring formation. Unlike S1P, these FTY720 analogs exhibit differential phosphorylation effects without altering the intracellular calcium level. Inhibitor studies indicate that barrier enhancement by these analogs involves signaling via Gi-coupled receptors, tyrosine kinases, and lipid rafts. Consistent with these in vitro responses, the (S)-phosphonate analog of FTY720 significantly reduces multiple indices of alveolar and vascular permeability in a lipopolysaccharide-mediated murine model of ALI (without significant alterations in leukocyte counts). These results demonstrate the capacity for FTY720 analogs to significantly decrease pulmonary vascular leakage and inflammation in vitro and in vivo.

Original languageEnglish (US)
Pages (from-to)54-64
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Volume331
Issue number1
DOIs
StatePublished - Oct 2009
Externally publishedYes

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Capillary Permeability
Lung
Endothelial Cells
Acute Lung Injury
Electric Impedance
Blood Vessels
Fingolimod Hydrochloride
In Vitro Techniques
1,3-propanediol
Receptor Protein-Tyrosine Kinases
Lung Injury
Leukocyte Count
Lipopolysaccharides
Actins
Phosphorylation
sphingosine 1-phosphate
Inflammation
Calcium
Lipids

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

Synthetic analogs of FTY720 [2-amino-2-(2-[4-octylphenyl]ethyl)-1,3- propanediol] differentially regulate pulmonary vascular permeability in vivo and in vitro. / Camp, S. M.; Bittman, R.; Chiang, E. T.; Moreno-Vinasco, L.; Mirzapoiazova, T.; Sammani, S.; Lu, X.; Sun, C.; Harbeck, M.; Roe, M.; Natarajan, V.; Garcia, Joe GN; Dudek, Steven M.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 331, No. 1, 10.2009, p. 54-64.

Research output: Contribution to journalArticle

Camp, SM, Bittman, R, Chiang, ET, Moreno-Vinasco, L, Mirzapoiazova, T, Sammani, S, Lu, X, Sun, C, Harbeck, M, Roe, M, Natarajan, V, Garcia, JGN & Dudek, SM 2009, 'Synthetic analogs of FTY720 [2-amino-2-(2-[4-octylphenyl]ethyl)-1,3- propanediol] differentially regulate pulmonary vascular permeability in vivo and in vitro', Journal of Pharmacology and Experimental Therapeutics, vol. 331, no. 1, pp. 54-64. https://doi.org/10.1124/jpet.109.153544
Camp, S. M. ; Bittman, R. ; Chiang, E. T. ; Moreno-Vinasco, L. ; Mirzapoiazova, T. ; Sammani, S. ; Lu, X. ; Sun, C. ; Harbeck, M. ; Roe, M. ; Natarajan, V. ; Garcia, Joe GN ; Dudek, Steven M. / Synthetic analogs of FTY720 [2-amino-2-(2-[4-octylphenyl]ethyl)-1,3- propanediol] differentially regulate pulmonary vascular permeability in vivo and in vitro. In: Journal of Pharmacology and Experimental Therapeutics. 2009 ; Vol. 331, No. 1. pp. 54-64.
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abstract = "Novel therapies are needed to address the vascular endothelial cell (EC) barrier disruption that occurs in inflammatory diseases such as acute lung injury (ALI). We previously demonstrated the potent barrier-enhancing effects of both sphingosine 1-phosphate (S1P) and the structurally similar compound FTY720 [2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol] in inflammatory lung injury. In this study, we examined the therapeutic potential of several novel FTY720 analogs to reduce vascular leak. Similar to S1P and FTY720, the (R)- and (S)-enantiomers of FTY720 phosphonate and enephosphonate analogs produce sustained EC barrier enhancement in vitro, as seen by increases in transendothelial electrical resistance (TER). In contrast, the (R)- and (S)-enantiomers of FTY720-regioisomeric analogs disrupt EC barrier integrity in a dose-dependent manner. Barrier-enhancing FTY720 analogs demonstrate a wider protective concentration range in vitro (1-50 μM) and greater potency than either S1P or FTY720. In contrast to FTY720-induced EC barrier enhancement, S1P and the FTY720 analogs dramatically increase TER within minutes in association with cortical actin ring formation. Unlike S1P, these FTY720 analogs exhibit differential phosphorylation effects without altering the intracellular calcium level. Inhibitor studies indicate that barrier enhancement by these analogs involves signaling via Gi-coupled receptors, tyrosine kinases, and lipid rafts. Consistent with these in vitro responses, the (S)-phosphonate analog of FTY720 significantly reduces multiple indices of alveolar and vascular permeability in a lipopolysaccharide-mediated murine model of ALI (without significant alterations in leukocyte counts). These results demonstrate the capacity for FTY720 analogs to significantly decrease pulmonary vascular leakage and inflammation in vitro and in vivo.",
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AU - Chiang, E. T.

AU - Moreno-Vinasco, L.

AU - Mirzapoiazova, T.

AU - Sammani, S.

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AU - Sun, C.

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