Department of Medicine, Imperial College School of Medicine, London, UK.
J Clin Endocrinol Metab. 2021 Mar 8;106(3):622-635. doi: 10.1210/clinem/dgaa874.
This paper attempts to explain how the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus causes the complications that make coronavirus disease 2019 (COVID-19) a serious disease in specific patient subgroups. It suggests that cortisol-associated activation of the mineralocorticoid receptor (MR) in epithelial and endothelial cells infected with the virus stimulates the release of adenosine 5'-triphosphate (ATP), which then acts back on purinergic receptors. In the lung this could produce the nonproductive cough via purinergic P2X3 receptors on vagal afferent nerves. In endothelial cells it could stimulate exocytosis of Weibel-Palade bodies (WPBs) that contain angiopoietin-2, which is important in the pathogenesis of acute respiratory distress syndrome (ARDS) by increasing capillary permeability and von Willebrand factor (VWF), which mediates platelet adhesion to the endothelium and hence clotting. Angiopoietin-2 and VWF levels both are markedly elevated in COVID-19-associated ARDS. This paper offers an explanation for the sex differences in SARS-CoV-2 complications and also for why these are strongly associated with age, race, diabetes, and body mass index. It also explains why individuals with blood group A have a higher risk of severe infection than those with blood group O. Dexamethasone has been shown to be of benefit in coronavirus ARDS patients and has been thought to act as an anti-inflammatory drug. This paper suggests that a major part of its effect may be due to suppression of cortisol secretion. There is an urgent need to trial the combination of dexamethasone and an MR antagonist such as spironolactone to more effectively block the MR and hence the exocytosis of WPBs.
本文试图解释严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）病毒如何导致并发症，使 2019 年冠状病毒病（COVID-19）成为特定患者亚群中的严重疾病。它表明，受病毒感染的上皮细胞和内皮细胞中与皮质醇相关的盐皮质激素受体（MR）的激活刺激了三磷酸腺苷（ATP）的释放，然后 ATP 反过来作用于嘌呤能受体。在肺部，这可能通过迷走传入神经上的嘌呤能 P2X3 受体产生非生产性咳嗽。在内皮细胞中，它可以刺激包含血管生成素-2 的 Weibel-Palade 体（WPB）的胞吐作用，血管生成素-2 通过增加毛细血管通透性和血管性血友病因子（VWF）在急性呼吸窘迫综合征（ARDS）的发病机制中起重要作用，VWF 介导血小板与内皮的黏附，从而导致凝血。血管生成素-2 和 VWF 水平在 COVID-19 相关 ARDS 中均明显升高。本文为 SARS-CoV-2 并发症中的性别差异以及为什么这些差异与年龄、种族、糖尿病和体重指数密切相关提供了一个解释。它还解释了为什么血型 A 的个体比血型 O 的个体感染严重的风险更高。地塞米松已被证明对冠状病毒性 ARDS 患者有效，并被认为是一种抗炎药物。本文认为，其部分作用可能是由于抑制了皮质醇的分泌。迫切需要试验地塞米松和 MR 拮抗剂（如螺内酯）的联合使用，以更有效地阻断 MR，从而阻断 WPB 的胞吐作用。
