Direct endothelial ENaC activation mitigates vasculopathy induced by SARS-CoV2 spike protein.
Direct endothelial ENaC activation mitigates vasculopathy induced by SARS-CoV2 spike protein.
复制标题
内皮细胞ENaC的直接激活可减轻SARS-CoV2刺突蛋白诱导的血管病变。
DOI：
10.3389/fimmu.2023.1241448
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发表时间：
2023
影响因子：
7.3
通讯作者：
Lucas, Rudolf
中科院分区：
文献类型：
--
作者：
Romero, Maritza J.;Yue, Qian;Singla, Bhupesh;Hamacher, Juerg;Sridhar, Supriya;Moseley, Auriel S.;Song, Chang;Mraheil, Mobarak A.;Fischer, Bernhard;Zeitlinger, Markus;Chakraborty, Trinad;Fulton, David;Gan, Lin;Annex, Brian H.;Csanyi, Gabor;Eaton, Douglas C.;Lucas, Rudolf
关键词：
尽管COVID-19和非COVID-19 ARDS均可伴有循环细胞因子水平显著升高，但前者与后者的显著不同之处在于其较高的血管病变，其特征为肺毛细血管中氧化应激和凝血障碍增加。这表明存在SARS-CoV 2特异性因子和机制，可以使内皮细胞变得功能障碍。虽然该病毒很少在内皮细胞或循环中检测到，但其刺突蛋白的S1亚基（包含人ACE 2（hACE 2）的受体结合结构域（RBD））可以在COVID-19患者的血浆中检测到，其水平与疾病严重程度相关。目前还不清楚SARS-CoV 2 RBD如何在肺内皮中发挥其有害作用，以及是否存在减轻这种作用的机制。在这项研究中，我们使用的RBD处理的人肺微血管内皮细胞（HL-MVEC），包括电生理学，屏障功能，氧化应激和人ACE 2（hACE 2）表面蛋白表达的测量与在转基因小鼠体内研究的组合全球表达人ACE 2和注射RBD。我们发现，SARS-CoV 2 RBD损害内皮ENaC活性，减少表面hACE 2表达，并增加HL-MVEC单层中活性氧（ROS）和组织因子（TF）的产生，从而促进屏障功能障碍和凝血障碍。TNF衍生的TIP肽（a.k.a. solnatide，AP 301）-其在结合至其α亚基后直接激活ENaC-可以克服RBD诱导的ENaC功能和hACE 2表达的损害，减轻ROS和TF产生并恢复HL-MVEC单层中的屏障功能。与COVID-19患者合并感染S.与单纯感染SARS-CoV 2的受试者相比，我们观察到，在全身表达hACE 2的转基因小鼠中，在腹膜内滴注S.肺炎，并且这通过TIP肽治疗减轻。
Although both COVID-19 and non-COVID-19 ARDS can be accompanied by significantly increased levels of circulating cytokines, the former significantly differs from the latter by its higher vasculopathy, characterized by increased oxidative stress and coagulopathy in lung capillaries. This points towards the existence of SARS-CoV2-specific factors and mechanisms that can sensitize the endothelium towards becoming dysfunctional. Although the virus is rarely detected within endothelial cells or in the circulation, the S1 subunit of its spike protein, which contains the receptor binding domain (RBD) for human ACE2 (hACE2), can be detected in plasma from COVID-19 patients and its levels correlate with disease severity. It remains obscure how the SARS-CoV2 RBD exerts its deleterious actions in lung endothelium and whether there are mechanisms to mitigate this. In this study, we use a combination of in vitro studies in RBD-treated human lung microvascular endothelial cells (HL-MVEC), including electrophysiology, barrier function, oxidative stress and human ACE2 (hACE2) surface protein expression measurements with in vivo studies in transgenic mice globally expressing human ACE2 and injected with RBD. We show that SARS-CoV2 RBD impairs endothelial ENaC activity, reduces surface hACE2 expression and increases reactive oxygen species (ROS) and tissue factor (TF) generation in monolayers of HL-MVEC, as such promoting barrier dysfunction and coagulopathy. The TNF-derived TIP peptide (a.k.a. solnatide, AP301) -which directly activates ENaC upon binding to its a subunit- can override RBD-induced impairment of ENaC function and hACE2 expression, mitigates ROS and TF generation and restores barrier function in HL-MVEC monolayers. In correlation with the increased mortality observed in COVID-19 patients co-infected with S. pneumoniae, compared to subjects solely infected with SARS-CoV2, we observe that prior intraperitoneal RBD treatment in transgenic mice globally expressing hACE2 significantly increases fibrin deposition and capillary leak upon intratracheal instillation of S. pneumoniae and that this is mitigated by TIP peptide treatment.
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影响因子：
5.8
作者：
Hattori Y;Hattori K;Machida T;Matsuda N
通讯作者：
Matsuda N
影响因子：
7.3
作者：
Hamacher J;Hadizamani Y;Borgmann M;Mohaupt M;Männel DN;Moehrlen U;Lucas R;Stammberger U
通讯作者：
Stammberger U
影响因子：
11.8
作者：
Amin-Chowdhury, Zahin;Aiano, Felicity;Ladhani, Shamez N.
通讯作者：
Ladhani, Shamez N.
DOI：
10.1164/rccm.201405-0833oc
发表时间：
2014-09-01
影响因子：
24.7
作者：
Czikora, Istvan;Alli, Abdel;Lucas, Rudolf
通讯作者：
Lucas, Rudolf
影响因子：
15.1
作者：
Krenn, Katharina;Lucas, Rudolf;Ullrich, Roman
通讯作者：
Ullrich, Roman