title: EPHA4-FC TREATMENT REDUCES ISCHEMIA/REPERFUSION-INDUCED INTESTINAL INJURY BY INHIBITING VASCULAR PERMEABILITY.
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.
authors.affiliation: *School of Biomedical Sciences, The University of Queensland, St Lucia †Royal Brisbane and Women's Hospital and The University of Queensland ‡Leukaemia Foundation Laboratory, QIMR Berghofer Medical Research Institute, Herston §Paediatric Intensive Care Unit, Lady Cilento Children's Hospital ||Academic Discipline of Paediatrics and Child Health, School of Medicine, The University of Queensland, Lady Cilento Children's Hospital, South Brisbane, Queensland, Australia.
authors.forename: Trent M
authors.initials: TM
authors.lastname: Woodruff
authors.forename: Mike C-L
authors.initials: MC
authors.lastname: Wu
authors.forename: Michael
authors.initials: M
authors.lastname: Morgan
authors.forename: Nathan T
authors.initials: NT
authors.lastname: Bain
authors.forename: Angela
authors.initials: A
authors.lastname: Jeanes
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Lipman
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ting
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Boyd
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Taylor
authors.forename: Mark G
authors.initials: MG
authors.lastname: Coulthard
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D002460:Cell Line; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D036122:Receptor, EphA4 / Q000037:antagonists & inhibitors*; D015427:Reperfusion Injury / Q000188:drug therapy*; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D007141:Immunoglobulin Fc Fragments; D014409:Tumor Necrosis Factor-alpha; D036122:Receptor, EphA4