白细胞介素-6 在 COVID-19 和细菌性败血症中驱动内皮糖萼损伤

IF 9.2 1区 医学 Q1 PERIPHERAL VASCULAR DISEASE Angiogenesis Pub Date : 2024-04-10 DOI:10.1007/s10456-024-09916-w
Carolin Christina Drost, Alexandros Rovas, Irina Osiaevi, Klaus Schughart, Alexander Lukasz, Wolfgang A. Linke, Hermann Pavenstädt, Philipp Kümpers
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引用次数: 0

摘要

内皮糖萼(eGC)的损伤在全身炎症期间血管高渗透性和器官损伤的发展中起着核心作用。然而,eGC损伤的具体信号通路仍未明确。本研究旨在结合舌下视频显微镜、血浆蛋白质组学和活细胞成像技术,进一步揭示2019年冠状病毒病(COVID-19)或细菌性败血症患者的eGC损伤途径。这项前瞻性多中心MICROCODE研究的二次分析包括22名COVID-19患者、43名入住中级或重症监护病房的细菌性败血症患者以及10名健康对照组。白细胞介素-6(IL-6)与受损的eGC密切相关,并与eGC尺寸(rs=0.36,p=0.0015)和循环中的eGC生物标志物相关。在体外,IL-6会降低eGC的高度和覆盖率,而用抗IL-6受体抗体托西珠单抗或Janus激酶抑制剂托法替尼阻断IL-6信号可抑制这种降低。将内皮细胞暴露于来自COVID-19或脓毒症患者的5%血清中会导致eGC高度显著下降,而与托珠单抗共孵育可减轻这种下降。在麻省总医院 219 名患者组成的 COVID-19 外部队列中,先前确定的蛋白质组 eGC 特征与 IL-6 相关(rs=-0.58,p <0.0001),并可预测 28 天死亡率和/或插管的综合终点(ROC-AUC:0.86 [95% CI:0.81-0.91],p <0.001)。这些数据表明,在 COVID-19 和细菌性败血症中,IL-6 可能会显著驱动 eGC 损伤。我们的研究结果为了解全身性炎症期间血管功能障碍的病理机制提供了有价值的见解,并强调了进一步开展体内研究的必要性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Interleukin-6 drives endothelial glycocalyx damage in COVID-19 and bacterial sepsis

Damage of the endothelial glycocalyx (eGC) plays a central role in the development of vascular hyperpermeability and organ damage during systemic inflammation. However, the specific signalling pathways for eGC damage remain poorly defined. Aim of this study was to combine sublingual video-microscopy, plasma proteomics and live cell imaging to uncover further pathways of eGC damage in patients with coronavirus disease 2019 (COVID-19) or bacterial sepsis. This secondary analysis of the prospective multicenter MICROCODE study included 22 patients with COVID-19 and 43 patients with bacterial sepsis admitted to intermediate or intensive care units and 10 healthy controls. Interleukin-6 (IL-6) was strongly associated with damaged eGC and correlated both with eGC dimensions (rs=0.36, p = 0.0015) and circulating eGC biomarkers. In vitro, IL-6 reduced eGC height and coverage, which was inhibited by blocking IL-6 signalling with the anti-IL-6 receptor antibody tocilizumab or the Janus kinase inhibitor tofacitinib. Exposure of endothelial cells to 5% serum from COVID-19 or sepsis patients resulted in a significant decrease in eGC height, which was attenuated by co-incubation with tocilizumab. In an external COVID-19 cohort of 219 patients from Massachusetts General Hospital, a previously identified proteomic eGC signature correlated with IL-6 (rs=-0.58, p < 0.0001) and predicted the combined endpoint of 28-day mortality and/or intubation (ROC-AUC: 0.86 [95% CI: 0.81–0.91], p < 0.001). The data suggest that IL-6 may significantly drive eGC damage in COVID-19 and bacterial sepsis. Our findings provide valuable insights into pathomechanisms of vascular dysfunction during systemic inflammation and highlight the need for further in vivo studies.

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来源期刊
Angiogenesis
Angiogenesis PERIPHERAL VASCULAR DISEASE-
CiteScore
21.90
自引率
8.20%
发文量
37
审稿时长
6-12 weeks
期刊介绍: Angiogenesis, a renowned international journal, seeks to publish high-quality original articles and reviews on the cellular and molecular mechanisms governing angiogenesis in both normal and pathological conditions. By serving as a primary platform for swift communication within the field of angiogenesis research, this multidisciplinary journal showcases pioneering experimental studies utilizing molecular techniques, in vitro methods, animal models, and clinical investigations into angiogenic diseases. Furthermore, Angiogenesis sheds light on cutting-edge therapeutic strategies for promoting or inhibiting angiogenesis, while also highlighting fresh markers and techniques for disease diagnosis and prognosis.
期刊最新文献
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