EPHA4-FC treatment reduces ischemia/reperfusion-induced intestinal injury by inhibiting vascular permeability

Woodruff, Trent M., Wu, Mike C.-L., Morgan, Michael, Bain, Nathan T., Jeanes, Angela, Lipman, Jeffrey, Ting, Michael J., Boyd, Andrew W., Taylor, Stephen M. and Coulthard, Mark G. (2016) EPHA4-FC treatment reduces ischemia/reperfusion-induced intestinal injury by inhibiting vascular permeability. Shock, 45 2: 184-191. doi:10.1097/SHK.0000000000000494

Author Woodruff, Trent M.
Wu, Mike C.-L.
Morgan, Michael
Bain, Nathan T.
Jeanes, Angela
Lipman, Jeffrey
Ting, Michael J.
Boyd, Andrew W.
Taylor, Stephen M.
Coulthard, Mark G.
Title EPHA4-FC treatment reduces ischemia/reperfusion-induced intestinal injury by inhibiting vascular permeability
Journal name Shock   Check publisher's open access policy
ISSN 1540-0514
Publication date 2016-02-01
Year available 2016
Sub-type Article (original research)
DOI 10.1097/SHK.0000000000000494
Open Access Status Not Open Access
Volume 45
Issue 2
Start page 184
End page 191
Total pages 8
Place of publication Philadelphia, PA United States
Publisher Lippincott Williams & Wilkins
Language eng
Subject 2711 Emergency Medicine
2706 Critical Care and Intensive Care Medicine
Abstract ABSTRACT: The inflammatory response is characterized by increased endothelial permeability, which permits the passage of fluid and inflammatory cells into interstitial spaces. The Eph/ephrin receptor ligand system plays a role in inflammation through a signaling cascade, which modifies Rho-GTPase activity. We hypothesized that blocking Eph/ephrin signaling using an EphA4-Fc would result in decreased inflammation and tissue injury in a model of ischemia/reperfusion (I/R) injury. Mice undergoing intestinal I/R pretreated with the EphA4-Fc had significantly reduced intestinal injury compared to mice injected with the control Fc. This reduction in I/R injury was accompanied by significantly reduced neutrophil infiltration, but did not affect intestinal inflammatory cytokine generation. Using microdialysis, we identified that intestinal I/R induced a marked increase in systemic vascular leakage, which was completely abrogated in EphA4-Fc-treated mice. Finally, we confirmed the direct role of Eph/ephrin signaling in endothelial leakage by demonstrating that EphA4-Fc inhibited tumor necrosis factor-[alpha]–induced vascular permeability in human umbilical vein endothelial cells. This study identifies that Eph/ephrin interaction induces proinflammatory signaling in vivo by inducing vascular leak and neutrophil infiltration, which results in tissue injury in intestinal I/R. Therefore, therapeutic targeting of Eph/ephrin interaction using inhibitors, such as EphA4-Fc, may be a novel method to prevent tissue injury in acute inflammation by influencing endothelial integrity and by controlling vascular leak.
Keyword Eph
Gut IR
Vascular Leak
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID APP1021413
Institutional Status UQ

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Sub-type: Article (original research)
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