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Erythropoietin-producing hepatocellular carcinoma (Eph) receptors and their ephrin ligands play a key role in vascular endothelial barrier disruption but are currently not a therapeutic target in sepsis. Using a cecal ligation and puncture (CLP) mouse model of sepsis, we showed that prophylactic or therapeutic treatment of mice with EphA4-Fc, a decoy receptor and pan-ephrin inhibitor, resulted in improved survival and a reduction in vascular leak, lung injury, and endothelial cell dysfunction.\n            <jats:italic>EphA2<\/jats:italic>\n            <jats:sup>\n              <jats:italic>\u2212\/\u2212<\/jats:italic>\n            <\/jats:sup>\n            mice also exhibited reduced mortality and pathology after CLP compared with wild-type mice. Proteomics of plasma samples from mice with sepsis after CLP revealed dysregulation of a number of Eph\/ephrins, including EphA2\/ephrin A1. Administration of EphA4-Fc to cultured human endothelial cells pretreated with TNF-\u03b1 or ephrin-A1 prevented loss of endothelial junction proteins, specifically VE-cadherin, with maintenance of endothelial barrier integrity. In children admitted to hospital with fever and suspected infection, we observed that changes in EphA2\/ephrin A1 in serum samples correlated with endothelial and organ dysfunction. Targeting Eph\/ephrin signaling may be a potential therapeutic strategy to reduce sepsis-induced endothelial dysfunction and mortality.\n          <\/jats:p>","DOI":"10.1126\/scitranslmed.adg5768","type":"journal-article","created":{"date-parts":[[2024,4,24]],"date-time":"2024-04-24T17:58:10Z","timestamp":1713981490000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":31,"title":["Inhibiting Eph\/ephrin signaling reduces vascular leak and endothelial cell dysfunction in mice with sepsis"],"prefix":"10.1126","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1819-3459","authenticated-orcid":true,"given":"Nemat","family":"Khan","sequence":"first","affiliation":[{"name":"School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Brisbane, QLD 4072, Australia."},{"name":"Mayne Academy of Paediatrics, Faculty of Medicine, University of Queensland, Queensland Children\u2019s Hospital, Brisbane, QLD 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