Endotheliopathy and liver injury in COVID-19

COVID-19 中的内皮病和肝损伤

• 批准号: 10662455
• 负责人: YASUKO IWAKIRI
• 金额: $ 41.88万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 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/10662455
• 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; Inflammatory; Injections; Injury; Interleukin 6 Receptor; Interleukin-6; JAK1 gene; Liver; Membrane; Microcirculation; Modeling; Morbidity - disease rate; Murine hepatitis virus; Mus; Outcome; Pathway interactions; Patients; Plasma; Production; Prognosis; Reporting; SARS-CoV-2 infection; STAT3 gene; Signal Induction; Signal Pathway; Signal Transduction; System; Testing; Therapeutic; Thrombosis; Time; Tissues; cytokine; endothelial dysfunction; in vivo; inhibitor; liver injury; lung failure; lung injury; mortality; mouse model; new therapeutic target; novel therapeutic intervention; novel therapeutics; therapeutic target; thrombotic complications; transcriptome sequencing; transcriptomics; von Willebrand Factor

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是由SARS-CoV-2感染引起的多系统疾病。呼吸道细胞中的SARS-CoV-2感染