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.

中文翻译：

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抑制 Eph/ephrin 信号传导可减少脓毒症小鼠的血管渗漏和内皮细胞功能障碍

败血症是一种危及生命的疾病，由宿主对感染的反应失调引起，每年导致全球 1100 万人死亡。血管内皮细胞功能障碍导致内皮屏障完整性丧失，从而导致脓毒症引起的多器官衰竭和死亡。产生促红细胞生成素的肝细胞癌 (Eph) 受体及其肝配蛋白配体在血管内皮屏障破坏中发挥关键作用，但目前不是脓毒症的治疗靶点。使用脓毒症盲肠结扎穿刺 (CLP) 小鼠模型，我们发现用 EphA4-Fc（一种诱饵受体和泛肝配蛋白抑制剂）对小鼠进行预防性或治疗性治疗，可提高生存率并减少血管渗漏、肺损伤和内皮细胞功能障碍。与野生型小鼠相比，EphA2 ^-/−小鼠在 CLP 后还表现出死亡率和病理学降低。 CLP 后脓毒症小鼠血浆样本的蛋白质组学显示许多 Eph/ephrins 失调，包括 EphA2/ephrin A1。将 EphA4-Fc 给予经 TNF-α 或肝配蛋白-A1 预处理的培养人内皮细胞，可防止内皮连接蛋白（特别是 VE-钙粘蛋白）的损失，同时维持内皮屏障的完整性。在因发烧和疑似感染而入院的儿童中，我们观察到血清样本中 EphA2/ephrin A1 的变化与内皮和器官功能障碍相关。靶向 Eph/ephrin 信号传导可能是减少脓毒症引起的内皮功能障碍和死亡率的潜在治疗策略。