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    Sphingosine-1-phosphate receptor-independent lung endothelial cell barrier disruption induced by FTY720 regioisomers

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    Author
    Camp, Sara M
    Marciniak, Alexander
    Chiang, Eddie T
    Garcia, Alexander N
    Bittman, Robert
    Polt, Robin
    Perez, Ruth G
    Dudek, Steven M
    Garcia, Joe G N
    Affiliation
    Univ Arizona, Dept Med,
    Univ Arizona, Dept Chem & Biochem
    Univ Arizona, Dept Radiat Oncol
    Issue Date
    2020-02-10
    Keywords
    FTY720
    acute respiratory distress syndrome
    endothelial
    permeability
    regioisomer
    sphingosine 1-phosphate
    
    Metadata
    Show full item record
    Publisher
    SAGE PUBLICATIONS INC
    Citation
    Camp, S. M., Marciniak, A., Chiang, E. T., Garcia, A. N., Bittman, R., Polt, R., … Garcia, J. G. N. (2020). Sphingosine-1-phosphate receptor-independent lung endothelial cell barrier disruption induced by FTY720 regioisomers. Pulmonary Circulation. https://doi.org/10.1177/2045894020905521
    Journal
    PULMONARY CIRCULATION
    Rights
    Copyright © The Author(s) 2020. Article reuse guidelines: sagepub.com/journals-permissions journals.sagepub.com/home/pul. Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
    Collection Information
    This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.
    Abstract
    Rationale Vascular permeability is a hallmark of acute respiratory distress syndrome (ARDS) and ventilator-induced lung injury pathobiology; however, the mechanisms underlying this vascular dysregulation remain unclear, thereby impairing the development of desperately needed effective therapeutics. We have shown that sphingosine-1-phosphate (S1P) and 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol (FTY720) analogues are useful tools for exploring vascular barrier regulation mechanisms. Objective To experimentally define the effects of FTY720 regioisomers on lung endothelial cell barrier regulation. Methods Specific barrier-regulatory receptor and kinase inhibitors were utilized to probe signaling mechanisms involved in FTY720 regioisomer-mediated human lung endothelial cell barrier responses (trans-endothelial electrical resistance, TER). Docking simulations with the S1P1 receptor were performed to further evaluate FTY720 regioisomer signaling. Results FTY720 regioisomers produced potent endothelial cell barrier disruption reflected by declines in TER alterations. Pharmacologic inhibition of Gi-coupled S1P receptors (S1P1, S1P2, S1P3) failed to alter FTY720 regioisomer-mediated barrier disruption; findings that were corroborated by docking simulations demonstrating FTY720 regiosomers were repelled from S1P1 docking, in contrast to strong S1P1 binding elicited by S1P. Inhibition of either the barrier-disrupting PAR-1 receptor, the VEGF receptor, Rho-kinase, MAPK, NFkB, or PI3K failed to alter FTY720 regioisomer-induced endothelial cell barrier disruption. While FTY720 regioisomers significantly increased protein phosphatase 2 (PP2A) activity, PP2A inhibitors failed to alter FTY720 regioisomer-induced endothelial cell barrier disruption. Conclusions Together, these results imply a vexing model of pulmonary vascular barrier dysregulation in response to FTY720-related compounds and highlight the need for further insights into mechanisms of vascular integrity required to promote the development of novel therapeutic tools to prevent or reverse the pulmonary vascular leak central to ARDS outcomes.
    Note
    Open access article
    ISSN
    2045-8932
    PubMed ID
    32096779
    DOI
    10.1177/2045894020905521
    Version
    Final published version
    ae974a485f413a2113503eed53cd6c53
    10.1177/2045894020905521
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