Stenmark Kurt R, Frid Maria G, Gerasimovskaya Evgenia, Zhang Hui, McCarthy Mary K, Thurman Joshua M, Morrison Thomas E
Divisions of Pediatric Critical Care Medicine and Cardiovascular Pulmonary Research, University of Colorado Denver, Denver, CO, USA.
Department of Immunology and Microbiology, University of Colorado Denver, Denver, CO, USA.
Pulm Circ. 2021 May 18;11(2):20458940211015799. doi: 10.1177/20458940211015799. eCollection 2021 Apr-Jun.
The outbreak of COVID-19 disease, caused by SARS-CoV-2 beta-coronovirus, urges a focused search for the underlying mechanisms and treatment options. The lung is the major target organ of COVID-19, wherein the primary cause of mortality is hypoxic respiratory failure, resulting from acute respiratory distress syndrome, with severe hypoxemia, often requiring assisted ventilation. While similar in some ways to acute respiratory distress syndrome secondary to other causes, lungs of some patients dying with COVID-19 exhibit distinct features of vascular involvement, including severe endothelial injury and cell death via apoptosis and/or pyroptosis, widespread capillary inflammation, and thrombosis. Furthermore, the pulmonary pathology of COVID-19 is characterized by focal inflammatory cell infiltration, impeding alveolar gas exchange resulting in areas of local tissue hypoxia, consistent with potential amplification of COVID-19 pathogenicity by hypoxia. Vascular endothelial cells play essential roles in both innate and adaptive immune responses, and are considered to be "conditional innate immune cells" centrally participating in various inflammatory, immune pathologies. Activated endothelial cells produce cytokines/chemokines, dynamically recruit and activate inflammatory cells and platelets, and centrally participate in pro-thrombotic processes (thrombotic microangiopathies). Initial reports presented pathological findings of localized direct infection of vascular endothelial cells with SARS-CoV-2, yet emerging evidence does not support direct infection of endothelial or other vascular wall cell and thus widespread endothelial cell dysfunction and inflammation may be better explained as secondary responses to epithelial cell infection and inflammation. Endothelial cells are also actively engaged in a cross-talk with the complement system, the essential arm of innate immunity. Recent reports present evidence for complement deposition in SARS-CoV-2-damaged lung microcirculation, further strengthening the idea that, in severe cases of COVID-19, complement activation is an essential player, generating destructive hemorrhagic, capillaritis-like tissue damage, clotting, and hyperinflammation. Thus, complement-targeted therapies are actively in development. This review is intended to explore in detail these ideas.
由严重急性呼吸综合征冠状病毒2（SARS-CoV-2）β冠状病毒引起的2019冠状病毒病（COVID-19）疫情，促使人们集中探寻其潜在机制和治疗方案。肺是COVID-19的主要靶器官，其主要死亡原因是急性呼吸窘迫综合征导致的低氧性呼吸衰竭，伴有严重低氧血症，常需辅助通气。虽然在某些方面与其他原因引起的急性呼吸窘迫综合征相似，但一些死于COVID-19的患者的肺部表现出血管受累的独特特征，包括严重的内皮损伤以及通过凋亡和/或焦亡导致的细胞死亡、广泛的毛细血管炎症和血栓形成。此外，COVID-19的肺部病理学特征为局灶性炎性细胞浸润，阻碍肺泡气体交换，导致局部组织缺氧区域，这与缺氧可能放大COVID-19致病性相一致。血管内皮细胞在先天性和适应性免疫反应中均发挥重要作用，被认为是集中参与各种炎症和免疫病理过程的“条件性固有免疫细胞”。活化的内皮细胞产生细胞因子/趋化因子，动态募集并激活炎性细胞和血小板，并集中参与血栓形成过程（血栓性微血管病）。最初的报告呈现了SARS-CoV-2对血管内皮细胞进行局部直接感染的病理结果，但新出现的证据并不支持内皮细胞或其他血管壁细胞的直接感染，因此，广泛的内皮细胞功能障碍和炎症可能更好地解释为对上皮细胞感染和炎症的继发性反应。内皮细胞还积极参与与固有免疫的重要组成部分补体系统的相互作用。最近的报告提供了补体在SARS-CoV-2损伤的肺微循环中沉积的证据，进一步强化了这样一种观点，即在COVID-19重症病例中，补体激活是一个关键因素，会造成破坏性的出血、毛细血管炎样组织损伤、凝血和过度炎症反应。因此，针对补体的疗法正在积极研发中。本综述旨在详细探讨这些观点。
