Endotheliopathy and liver injury in COVID-19

COVID-19 中的内皮病和肝损伤

基本信息

批准号：
10468220
负责人：
YASUKO IWAKIRI
金额：
$ 41.88万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-11 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10468220
关键词：
2019-nCoV Adhesions Binding Biology Blood Blood Platelets COVID-19 COVID-19 patient COVID-19 treatment Cell physiology Cell surface Cells Clinical Coagulation Process Complex Coronavirus Disease Endothelial Cells Endothelium Factor VIII Functional disorder Goals IL-6 inhibitor IL6ST gene Immune response In Vitro Infection Injections Injury Interleukin 6 Receptor Interleukin-6 JAK1 gene Lead Liver Membrane Microcirculation Modeling Morbidity - disease rate Murine hepatitis virus Mus Outcome Pathway interactions Patients Plasma Production Prognosis Reporting Respiratory Failure SARS-CoV-2 infection STAT3 gene Signal Pathway Signal Transduction Testing Therapeutic Thrombosis Time Tissues cytokine endothelial dysfunction in vivo inhibitor liver injury lung injury mortality mouse model new therapeutic target novel therapeutic intervention novel therapeutics therapeutic target thrombotic complications transcriptome sequencing transcriptomics von Willebrand Factor

项目摘要

COVID-19, caused by SARS-CoV-2 infection, is a multisystem disease. SARS-CoV-2 infection in airway cells and other tissues results in excessive production of proinflammatory cytokines, which can lead to pulmonary failure. The lung damage is caused in part by thrombotic complications from endotheliopathy, a form of endothelial dysfunction characterized by a proinflammatory and procoagulant state. This is a major cause of morbidity and mortality in patients with COVID-19. Clinical liver injury is often observed in COVID-19 and is associated with a worse prognosis than in patients without liver injury, but the pathophysiology remains unknown. The goal of our proposal is to determine the mechanism of liver injury in COVID-19. The presence of thrombosis was reported in the livers of COVID-19 patients. We found that liver injury (ALT greater than three times the upper limit of normal) is associated with an increase in procoagulant factors in the blood (n=3,830) and in liver tissue (n=48) from COVID-19 patients. Given that endotheliopathy activates the coagulation cascade and leads to platelet adhesion to the endothelium, which promotes thrombosis, we hypothesize that an excessive immune response to SARS-CoV-2 infection leads to endotheliopathy in the liver microcirculation, causing liver injury. IL-6 is a proinflammatory cytokine that is highly elevated in the blood of COVID-19 patients. We found that IL-6 levels were significantly higher in COVID-19 patients with liver injury than those without. IL-6 levels also positively correlated with plasma levels of von Willebrand factor (vWF), an indicator of endotheliopathy. IL-6 can initiate intracellular signaling both through a membrane-bound IL-6 receptor (IL-6R) (classical IL-6 signaling) as well as by binding to soluble IL-6R (sIL-6R). The latter is known as IL-6 trans-signaling and allows IL-6 signaling into cells not expressing IL-6R on the cell surface, such as liver sinusoidal endothelial cells (LSECs), as long as they express gp130. We thus hypothesize that IL-6 trans-signaling causes LSEC endotheliopathy (a proinflammatory and procoagulant state) and liver injury observed in COVID-19 patients, and that blocking this pathway will ameliorate endotheliopathy. Two aims are proposed. Aim 1 Determine the mechanism of LSEC endotheliopathy that leads to liver injury in COVID-19. Aim 2 Determine potential therapeutic targets for LSEC endotheliopathy in COVID-19. New therapies for COVID-19 will be needed for a long time to come. Here we will examine in a mechanistic manner a new therapeutic strategy for COVID-19 and its endotheliopathy. Because IL-6 signaling is largely unexplored in ECs, findings from this study will advance our understanding of not only the mechanism of thrombosis in the liver microcirculation, but also EC biology in general. Further, our model of IL- 6 driven liver injury is likely to be highly broadly relevant to SARS-CoV-2 endothelial injury and could also provide attractive therapeutic targets.

COVID-19 由 SARS-CoV-2 感染引起，是一种多系统疾病。气道细胞中的 SARS-CoV-2 感染和其他组织导致促炎细胞因子的过量产生，这可能导致肺失败。肺损伤部分是由内皮病（一种形式的内皮病）引起的血栓并发症引起的。以促炎和促凝血状态为特征的内皮功能障碍。这是一个主要原因 COVID-19 患者的发病率和死亡率。 COVID-19 中经常观察到临床肝损伤，并且与没有肝损伤的患者相比，预后较差，但病理生理学仍然存在未知。我们提案的目标是确定 COVID-19 肝损伤的机制。据报道，COVID-19 患者的肝脏存在血栓。我们发现肝损伤（ALT 大于正常上限的三倍）与促凝血因子的增加有关 COVID-19 患者的血液 (n=3,830) 和肝组织 (n=48) 中。鉴于内皮病激活凝血级联反应导致血小板粘附到内皮上，从而促进血栓形成，我们假设对 SARS-CoV-2 感染的过度免疫反应会导致血管内皮病变影响肝脏微循环，引起肝损伤。 IL-6 是一种促炎细胞因子，在 COVID-19 患者的血液中高度升高。我们发现患有肝损伤的 COVID-19 患者中 IL-6 水平显着高于没有肝损伤的患者。 IL-6水平还与血管性血友病因子（vWF）（内皮病指标）的血浆水平呈正相关。 IL-6 可以通过膜结合 IL-6 受体 (IL-6R)（经典 IL-6 信号传导）以及与可溶性 IL-6R (sIL-6R) 结合。后者被称为 IL-6 反式信号传导允许 IL-6 信号传导至细胞表面不表达 IL-6R 的细胞，例如肝窦内皮细胞细胞（LSEC），只要它们表达 gp130。因此我们假设 IL-6 反式信号传导导致 LSEC 在 COVID-19 患者中观察到内皮病（促炎和促凝血状态）和肝损伤，阻断该通路将改善内皮病。提出了两个目标。目标 1 确定 LSEC 内皮病导致 COVID-19 肝损伤的机制。目标 2 确定 COVID-19 中 LSEC 内皮病的潜在治疗靶点。未来很长一段时间内都需要针对 COVID-19 的新疗法。在这里我们将检查机械方式为 COVID-19 及其内皮病提供了新的治疗策略。因为IL-6信号传导在 EC 中很大程度上尚未被探索，这项研究的结果将增进我们对以下方面的理解：肝脏微循环血栓形成的机制，也是EC生物学的一般。此外，我们的 IL 模型 6 驱动的肝损伤可能与 SARS-CoV-2 内皮损伤高度广泛相关，并且也可能提供有吸引力的治疗靶点。