| Autor: |
Khan N; School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Brisbane, QLD 4072, Australia.; Mayne Academy of Paediatrics, Faculty of Medicine, University of Queensland, Queensland Children's Hospital, Brisbane, QLD 4101, Australia., Kumar V; School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Brisbane, QLD 4072, Australia., Li P; School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Brisbane, QLD 4072, Australia.; Mayne Academy of Paediatrics, Faculty of Medicine, University of Queensland, Queensland Children's Hospital, Brisbane, QLD 4101, Australia., Schlapbach LJ; Children's Intensive Care Research Program, Child Health Research Centre, University of Queensland, Brisbane, QLD 4101, Australia.; Paediatric Intensive Care Unit, Queensland Children's Hospital, Brisbane, QLD 4101, Australia.; Department of Intensive Care and Neonatology, and Children's Research Center, University Children's Hospital Zürich, University of Zürich, 8032 Zürich, Switzerland., Boyd AW; Faculty of Medicine, University of Queensland, Brisbane, QLD 4006, Australia., Coulthard MG; Mayne Academy of Paediatrics, Faculty of Medicine, University of Queensland, Queensland Children's Hospital, Brisbane, QLD 4101, Australia.; Paediatric Intensive Care Unit, Queensland Children's Hospital, Brisbane, QLD 4101, Australia., Woodruff TM; School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Brisbane, QLD 4072, Australia. |
| Abstrakt: |
Sepsis is a life-threatening disease caused by a dysregulated host response to infection, resulting in 11 million deaths globally each year. Vascular endothelial cell dysfunction results in the loss of endothelial barrier integrity, which contributes to sepsis-induced multiple organ failure and mortality. 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. EphA2 -/- 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-α 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. |
