Elevated Cytokine Levels in Plasma of Patients with SARS-CoV-2 Do Not Contribute to Pulmonary Microvascular Endothelial Permeability.
Elevated Cytokine Levels in Plasma of Patients with SARS-CoV-2 Do Not Contribute to Pulmonary Microvascular Endothelial Permeability.
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DOI：
10.1128/spectrum.01671-21
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发表时间：
2022-02-23
影响因子：
3.7
通讯作者：
Annex BH
中科院分区：
文献类型：
--
作者：
Kovacs-Kasa A;Zaied AA;Leanhart S;Koseoglu M;Sridhar S;Lucas R;Fulton DJ;Vazquez JA;Annex BH
严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）感染可引起血管内皮细胞损伤，但其机制尚不清楚。我们试图确定SARS-CoV-2患者与对照组血浆诱导的细胞因子升高的频率和类型及其与内皮损伤的关系。将8名连续入选的急性SARS-CoV-2感染住院患者的血浆与对照组进行比较。使用ECIS（电细胞基质阻抗传感）对人肺微血管EC评价内皮细胞（EC）屏障完整性。来自所有SARS-CoV-2的血浆（但没有来自对照组的血浆）降低跨内皮阻力的程度大于肿瘤坏死因子-α（TNF-α）（试验的阳性对照）产生的水平。凝血酶、血管生成素2（Ang 2）和血管内皮生长因子（VEGF）、补体因子C3 a和C5 a以及刺突蛋白增加内皮通透性，但与SARS-CoV-2血浆相比，程度较低，持续时间较短。对血浆中测量的Ang 2、VEGF和15种细胞因子的分析显示，SARS-CoV-2患者之间存在显著的患者间差异。凝血酶抑制剂，单一的，或针对细胞因子，Ca 3和C5 a受体拮抗剂的中和抗体的组合，或与ACE 2抗体的预处理未能减少SARS-CoV-2血浆诱导的EC渗透性。SARS-CoV-2患者血浆对EC屏障的破坏作用易受热灭活的影响。急性SARS-CoV-2感染住院患者的血浆均会破坏肺微血管的完整性。没有预测的单一或一组细胞因子导致血管通透性增强，尽管这些因子是热不稳定的。一种尚未确定但有效的循环因子似乎导致SARS-CoV-2感染患者的EC破坏。重要性SARS-CoV-2患者的肺血管内皮损伤是发病率和死亡率的最重要原因之一，并与更严重的并发症有关，包括急性呼吸窘迫综合征（ARDS）和随后因多器官衰竭导致的死亡。我们已经证明，在8例连续的SARS-CoV-2患者中，没有选择内皮损伤的证据，稀释的血浆在体外诱导了强烈的肺微血管损伤。已知的内皮屏障破坏剂和提议的SARS-CoV-2内皮通透性增加介质诱导的通透性变化幅度较小，持续时间较SARS-CoV-2患者血浆短。对SARS-CoV-2患者血浆内皮细胞通透性的影响是热不稳定的。导致内皮通透性增加的主要血浆因子仍有待确定。我们的研究为进一步研究SARS-CoV-2感染导致血管损伤的潜在机制提供了一种可能的方法。
The vascular endothelial injury occurs in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, but the mechanisms are poorly understood. We sought to determine the frequency and type of cytokine elevations and their relationship to endothelial injury induced by plasma from patients with SARS-CoV-2 versus controls. Plasma from eight consecutively enrolled patients hospitalized with acute SARS-CoV-2 infection was compared to controls. Endothelial cell (EC) barrier integrity was evaluated using ECIS (electric cell-substrate impedance sensing) on human lung microvascular EC. Plasma from all SARS-CoV-2 but none from controls decreased transendothelial resistance to a greater degree than that produced by tumor necrosis factor-alpha (TNF-α), the positive control for the assay. Thrombin, angiopoietin 2 (Ang2), and vascular endothelial growth factor (VEGF), complement factor C3a and C5a, and spike protein increased endothelial permeability, but to a lesser extent and a shorter duration when compared to SARS-CoV-2 plasma. Analysis of Ang2, VEGF, and 15 cytokines measured in plasma revealed striking patient-to-patient variability within the SARS-CoV-2 patients. Pretreatment with thrombin inhibitors, single, or combinations of neutralizing antibodies against cytokines, Ca3 and C5a receptor antagonists, or with ACE2 antibody failed to lessen the SARS-CoV-2 plasma-induced EC permeability. The EC barrier destructive effects of plasma from patients with SARS-CoV-2 were susceptible to heat inactivation. Plasma from patients hospitalized with acute SARS-CoV-2 infection uniformly disrupts lung microvascular integrity. No predicted single, or set of, cytokine(s) accounted for the enhanced vascular permeability, although the factor(s) were heat-labile. A still unidentified but potent circulating factor(s) appears to cause the EC disruption in SARS-CoV-2 infected patients. IMPORTANCE Lung vascular endothelial injury in SARS-CoV-2 patients is one of the most important causes of morbidity and mortality and has been linked to more severe complications including acute respiratory distress syndrome (ARDS) and subsequent death due to multiorgan failure. We have demonstrated that in eight consecutive patients with SARS-CoV-2, who were not selected for evidence of endothelial injury, the diluted plasma-induced intense lung microvascular damage, in vitro. Known endothelial barrier-disruptive agents and proposed mediators of increased endothelial permeability in SARS-CoV-2, induced changes in permeability that were smaller in magnitude and shorter in duration than plasma from patients with SARS-CoV-2. The effect on endothelial cell permeability of plasma from patients with SARS-CoV-2 was heat-labile. The main plasma factor that causes the increased endothelial permeability remains to be identified. Our study provides a possible approach for future studies to understand the underlying mechanisms leading to vascular injury in SARS-CoV-2 infections.
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