Sphingosine-1-phosphate receptor-independent lung endothelial cell barrier disruption induced by FTY720 regioisomers
Author
Camp, Sara MMarciniak, 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
2020-02-10Keywords
FTY720acute respiratory distress syndrome
endothelial
permeability
regioisomer
sphingosine 1-phosphate
Metadata
Show full item recordPublisher
SAGE PUBLICATIONS INCCitation
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/10.1177/2045894020905521Journal
PULMONARY CIRCULATIONRights
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 articleISSN
2045-8932PubMed ID
32096779Version
Final published versionae974a485f413a2113503eed53cd6c53
10.1177/2045894020905521