ArticleThe Journal of pharmacology and experimental therapeutics2009
Synthetic analogs of FTY720 [2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol] differentially regulate pulmonary vascular permeability in vivo and in vitro.
Article in The Journal of pharmacology and experimental therapeutics, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 63 citations in OpenAlex.
- Extracellular Vesicles as Drivers of Lung Endothelial Dysfunction in ARDS: Mechanisms and Therapeutic Opportunities.Comprehensive Physiology · 2026Review
- Genetic and epigenetic regulation of cortactin (CTTN) by inflammatory factors and mechanical stress in human lung endothelial cells.Bioscience reports · 2024Article
- Deletion of sphingosine kinase 2 attenuates cigarette smoke-mediated chronic obstructive pulmonary disease-like symptoms by reducing lung inflammation.Biomolecules & biomedicine · 2023Article
- Alveolus analysis: a web browser-based tool to analyze lung intravital microscopy.BMC pulmonary medicine · 2022Article
- A cortactin CTTN coding SNP contributes to lung vascular permeability and inflammatory disease severity in African descent subjects.Translational research : the journal of laboratory and clinical medicine · 2022Article
- MRSA-induced endothelial permeability and acute lung injury are attenuated by FTY720 S-phosphonate.American journal of physiology. Lung cellular and molecular physiology · 2022Article
- Barrier maintenance by S1P during inflammation and sepsis.Tissue barriers · 2021Review
- Immunology of COVID-19 and disease-modifying therapies: The good, the bad and the unknown.European journal of neurology · 2021Review
- Sphingolipids as a Novel Therapeutic Target in Radiation-Induced Lung Injury.Cell biochemistry and biophysics · 2021Review
- The emerging role of FTY720 as a sphingosine 1-phosphate analog for the treatment of ischemic stroke: The cellular and molecular mechanisms.Brain and behavior · 2021Review
- Lysophospholipids in Lung Inflammatory Diseases.Advances in experimental medicine and biology · 2021Article
- A label-free impedance assay in endothelial cells differentiates the activation and desensitization properties of clinical S1PFEBS open bio · 2020Article
- FTY720 (Fingolimod) Ameliorates Brain Injury through Multiple Mechanisms and is a Strong Candidate for Stroke Treatment.Current medicinal chemistry · 2020Review
- Article
- Sphingolipids Signaling in Lamellipodia Formation and Enhancement of Endothelial Barrier Function.Current topics in membranes · 2018Article
- Article
- The Consequences of Overlapping G-Quadruplexes and i-Motifs in the Platelet-Derived Growth Factor Receptor β Core Promoter Nuclease Hypersensitive Element Can Explain the Unexpected Effects of Mutations and Provide Opportunities for Selective Targeting of Both Structures by Small Molecules To Downregulate Gene Expression.Journal of the American Chemical Society · 2017Article
- Differential elastic responses to barrier-altering agonists in two types of human lung endothelium.Biochemical and biophysical research communications · 2016Article
- Ceramide Signaling and Metabolism in Pathophysiological States of the Lung.Annual review of physiology · 2016Review
- Mechanism of Action and Clinical Potential of Fingolimod for the Treatment of Stroke.Frontiers in neurology · 2016Article
Corrections and comments
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Authors and funding
13 authors at 2 institutions in 1 country.
Funding
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 microM) 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 G(i)-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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.