EPHA4-FC TREATMENT REDUCES ISCHEMIA/REPERFUSION-INDUCED INTESTINAL INJURY BY INHIBITING VASCULAR PERMEABILITY. Issue 2 (February 2016)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: Shock. Volume 45:Issue 2(2016:Feb.)
• Publication Date: 2016-02
• Subjects: Eph -- Ephrin -- gut IR -- inflammation -- vascular leak; Shock -- Periodicals; Shock -- Periodicals; Choc (Pathologie) -- Périodiques; Shock; Periodicals; 616.0475
• DOI: 10.1097/SHK.0000000000000494
• Languages: English
• ISSNs: 1073-2322

Abstract

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-α–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.