Endotheliopathy and liver injury in COVID-19

新冠肺炎是由SARS-CoV-2感染引起的一种多系统疾病。SARS-CoV-2在呼吸道细胞中的感染 和其他组织导致促炎细胞因子的过度产生，这可能导致肺 失败了。肺损伤部分是由内皮病的血栓并发症引起的，内皮病是一种 以促炎症和促凝血状态为特征的内皮功能障碍。这是一个主要的原因 新冠肺炎患者的发病率和死亡率。临床肝损害常见于新冠肺炎和IS 与无肝损伤的患者相比预后更差，但病理生理学仍 未知。我们建议的目的是确定新冠肺炎肝损伤的机制。 据报道，新冠肺炎患者的肝脏中存在血栓形成。我们发现肝脏损伤 (丙氨酸氨基转移酶高于正常上限的三倍)与促凝血因子增加有关 新冠肺炎患者血(n=3,830)和肝组织(n=48)。鉴于内皮病会激活 凝血级联导致血小板与内皮细胞黏附，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导致血管内皮病变 肝脏微循环，造成肝脏损伤。 IL-6是一种促炎细胞因子，在新冠肺炎患者的血液中高度升高。我们发现 新冠肺炎有肝损害患者IL-6水平显著高于无肝损害患者。IL-6水平 还与血浆von Willebrand因子(VWF)水平呈正相关，vWF是血管内皮病变的指标。 IL-6可以通过膜结合的IL-6R(经典的IL-6)启动细胞内信号 信号)以及与可溶性IL-6R(sIL-6R)结合。后者称为IL-6反式信号转导和 允许IL-6信号进入细胞表面不表达IL-6R的细胞，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转导信号导致LSEC 新冠肺炎患者的内皮病变(一种促炎症和促凝血状态)和肝损伤， 阻断这一途径将会改善血管内皮细胞病变。提出了两个目标。 目的1探讨新冠肺炎大鼠肝内皮细胞病变致肝损伤的机制。 目的2确定新冠肺炎治疗结缔组织内皮病的潜在靶点。 新冠肺炎在未来很长一段时间内都需要新的疗法。在这里我们将在一个 机械化治疗新冠肺炎及其内皮病变的新策略.因为IL-6信号 在很大程度上是在ECs中未被探索的，这项研究的发现不仅将促进我们对 血栓形成的机制在肝脏微循环中，也是EC生物学的总称。此外，我们的IL模型- 6致肝损伤可能与SARS-CoV-2内皮损伤高度广泛相关，还可能 提供有吸引力的治疗靶点。

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.