败血症新药

诸平

Researchers say the new drug targets and restores the endothelial cells that line blood vessels. Image: Adobe.

据澳大利亚昆士兰大学（University of Queensland简称UQ）2024年5月9日提供的消息，该校开发治疗败血症新药(UQ develops new drug for sepsis)。

一种新药可以通过恢复患者血管的健康来预防败血症相关的器官衰竭和死亡。昆士兰大学和昆士兰儿童医院(Queensland Children’s Hospital简称QCH)的研究人员已经成功地在老鼠身上测试了这种一流的药物。相关研究结果于2024年4月24日已经在《科学转化医学》（Science Translational Medicine）杂志网站发表——Nemat Khan, Vinod Kumar, Pengcheng Li, Rapids Study Group, Luregn J. Schlapbach, Andrew W. Boyd, Mark G. Coulthard, Trent M. Woodruff. Inhibiting Eph/ephrin signaling reduces vascular leak and endothelial cell dysfunction in mice with sepsis. Science Translational Medicine, 2024, 16(744). DOI: 10.1126/scitranslmed.adg5768. Published: 24 Apr 2024.

昆士兰大学和昆士兰儿童医院儿科重症监护室（QCH ’s Paediatric Intensive Care Unit）的马克·库特哈德博士（Dr Mark Coulthard）说，使用人类血液样本进行临床前测试的结果也很有希望。

马克·库特哈德博士说:“败血症患者器官衰竭的原因是血管内皮细胞渗漏，导致异常的液体流动，最终关闭血液供应。我们已经确定了因发烧和疑似感染而入院的儿童血管损伤的标志物，以及细胞中与之相关的蛋白质信号通路。我们开发的药物针对这些相互作用，以恢复血管内皮细胞（vascular endothelial cells）的功能。”

昆士兰大学生物医学科学院（UQ’s School of Biomedical Sciences）的特伦特·伍德拉夫教授（Professor Trent Woodruff）说，这种新方法解决了器官衰竭的潜在原因，而之前不成功的尝试主要集中在免疫反应上。“败血症被称为‘制药公司的墓地’（’graveyard for the drug companies’），因为尽管投入了大量资源，进行了100多次临床试验，但仍然没有有效的治疗方法来改变宿主的反应，一种靶向并恢复血管内皮的药物可能会减少败血症引起的器官损伤和死亡。”

马克·库特哈德博士说，研究人员对临床前测试的结果感到鼓舞。他说:“我们对91名因发烧和疑似感染而入院的儿童的血液样本进行了药物测试，并注意到生物标志物的变化与我们在小鼠研究中的变化相似。这表明这种药物对人类也可能有效。需要进一步的研究，包括在其他动物模型中研究此药物及其在临床试验中的有效性。” 该研究小组还包括昆士兰大学生物医学科学学院的奈梅特·卡恩博士（Dr Nemat Khan），并得到了澳大利亚国家卫生和医学研究委员会（Australian National Health and Medical Research Council）、昆士兰大学和儿童医院基金会（The University of Queensland and the Children’s Hospital Foundation）的资助。

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Editor’s summary

Sepsis pathology involves the vascular endothelium, and erythropoietin-producing hepatocellular carcinoma (Eph) receptors and their ephrin ligands regulate endothelial barrier function. Khan et al. used EphA4-Fc, a decoy receptor and ephrin inhibitor, to treat mice after cecal ligation and puncture, which induces sepsis. Treatment increased survival and decreased lung pathology, inflammation, and vascular leak. Mice lacking the EphA2 gene had reduced sepsis pathology after cecal ligation and puncture. Protein-level changes in Eph/ephrins in mice with sepsis were reversed by EphA4-Fc treatment. In serum samples from children with fever and suspected infection, several Eph/ephrins and markers of endothelial dysfunction were increased compared with control individuals. Organ dysfunction scores were positively correlated with EphA2 and ephrin-A1 signaling in patients with bacterial or viral infection. Targeting Eph/ephrin signaling may be a therapeutic strategy to treat endothelial dysfunction in sepsis. —Brandon Berry

Abstract

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.