Endotheliopathy and liver injury in COVID-19

COVID-19由SARS-CoV-2感染引起，是一种多系统疾病。SARS-CoV-2感染气道细胞 和其他组织导致促炎细胞因子的过度产生，这可导致肺 失败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 以促炎和促凝血状态为特征的内皮功能障碍。这是造成 COVID-19患者的发病率和死亡率。在COVID-19中经常观察到临床肝损伤， 与无肝损伤的患者相比， 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患者的肝脏中存在血栓形成。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 在COVID-19患者的血液（n = 3，830）和肝脏组织（n = 48）中。考虑到内皮病变激活了 凝血级联反应，并导致血小板粘附到内皮细胞，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了 肝脏微循环，造成肝脏损伤。 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 有肝损伤的COVID-19患者的IL-6水平显著高于无肝损伤的患者。il-6水平 也与血管性血友病因子（vWF）的血浆水平正相关，vWF是内皮病的指标。 IL-6可以通过膜结合的IL-6受体（IL-6R）（经典的IL-6 信号传导）以及通过结合可溶性IL-6R（sIL-6R）。后者被称为IL-6反式信号传导， 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反式信号转导导致LSEC 在COVID-19患者中观察到的内皮病（促炎和促凝血状态）和肝损伤， 并且阻断该途径将改善内皮病变。提出了两个目标。 目的1确定导致COVID-19肝损伤的LSEC内皮病变的机制。 目的2确定COVID-19中LSEC内皮病的潜在治疗靶点。 在未来很长一段时间内都需要新的COVID-19疗法。在这里，我们将在一个 为COVID-19及其内皮病变提供了新的治疗策略。因为IL-6信号 在EC中基本上未被探索，这项研究的结果将促进我们对不仅是 肝微循环中的血栓形成机制，而且一般也是EC生物学。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， 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.