College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
College of Medicine, Alfaisal University, Riyadh, Saudi Arabia; Department of Comparative Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Med Hypotheses. 2020 Oct;143:109906. doi: 10.1016/j.mehy.2020.109906. Epub 2020 May 30.
Most COVID-19 infected individuals present with mild flu-like symptoms; however, 5-10% of cases suffer from life-threatening pneumonia and respiratory failure. The pathogenesis of SARS-CoV-2 and its pathology of associated acute lung injury (ALI), acute respiratory distress syndrome (ARDS), sepsis, coagulopathy and multiorgan failure is not known. SARS-CoV-2 is an envelope virus with S (spike), M (membrane), N (nucleocapsid) and E (envelop) proteins. In a closely related coronavirus (SARS-CoV), the transmembrane E protein exerts an important role in membrane-ionic transport through viroporins, deletion of which reduced levels of IL-1β and a remarkably reduced lung edema compared to wild type. IL-1β is generated by macrophages upon activation of intracellular NLRP3 (NOD-like, leucine rich repeat domains, and pyrin domain-containing protein 3), part of the functional NLRP3 inflammasome complex that detects pathogenic microorganisms and stressors, while neutrophils are enhanced by increasing levels of IL-1β. Expiring neutrophils undergo "NETosis", producing thread-like extracellular structures termed neutrophil extracellular traps (NETs), which protect against mild infections and microbes. However, uncontrolled NET production can cause acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), coagulopathy, multiple organ failure, and autoimmune disease. Herein, we present arguments underlying our hypothesis that IL-1β and NETs, mediated via NLRP3 inflammasomes, form a feed-forward loop leading to the excessive alveolar and endothelial damage observed in severe cases of COVID-19. Considering such assertions, we propose potential drug candidates that could be used to alleviate such pathologies. Considering that recent efforts to ascertain effective treatments of COVID-19 in severe patients has been less than successful, investigating novel avenues of treating this virus are essential.
大多数 COVID-19 感染者表现出轻微的流感样症状；然而，5-10%的病例患有危及生命的肺炎和呼吸衰竭。SARS-CoV-2 的发病机制及其相关急性肺损伤 (ALI)、急性呼吸窘迫综合征 (ARDS)、脓毒症、凝血功能障碍和多器官衰竭的病理学尚不清楚。SARS-CoV-2 是一种包膜病毒，具有 S（刺突）、M（膜）、N（核衣壳）和 E（包膜）蛋白。在一种密切相关的冠状病毒（SARS-CoV）中，跨膜 E 蛋白通过 viroporins 发挥重要的膜离子转运作用，与野生型相比，缺失该蛋白会降低 IL-1β 的水平并显著减少肺水肿。IL-1β 是巨噬细胞在细胞内 NLRP3（NOD 样、富含亮氨酸重复结构域和吡喃结构域蛋白 3）被激活时产生的，NLRP3 炎症小体复合物的一部分，可检测到致病微生物和应激源，而中性粒细胞则通过增加 IL-1β 的水平增强。即将死亡的中性粒细胞经历“NETosis”，产生称为中性粒细胞胞外陷阱（NETs）的线状细胞外结构，可抵抗轻度感染和微生物。然而，不受控制的 NET 产生会导致急性肺损伤 (ALI) 和急性呼吸窘迫综合征 (ARDS)、凝血功能障碍、多器官衰竭和自身免疫性疾病。在此，我们提出了一个假设，即 IL-1β 和 NETs 通过 NLRP3 炎症小体介导，形成一个正反馈回路，导致 COVID-19 重症患者中观察到的肺泡和内皮过度损伤。考虑到这些说法，我们提出了一些潜在的药物候选物，这些候选物可能用于缓解这种病理。鉴于最近在确定 COVID-19 重症患者的有效治疗方法方面的努力不太成功，研究治疗这种病毒的新途径至关重要。
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