Hammersmith Hospital, Imperial College, London, United Kingdom.
Clinical Pharmacology Department, Vinnytsia National Pirogov Memorial Medical University, Vinnytsia, Ukraine.
Front Endocrinol (Lausanne). 2021 Nov 18;12:747744. doi: 10.3389/fendo.2021.747744. eCollection 2021.
This paper suggests that ATP release induced by the SARS-CoV-2 virus plays a key role in the genesis of the major symptoms and complications of COVID-19. Infection of specific cells which contain the Angiotensin-Converting Enzyme 2 (ACE2) receptor results in a loss of protection of the Mineralocorticoid Receptor (MR). Local activation by cortisol stimulates the release of ATP initially into the basolateral compartment and then by lysosomal exocytosis from the cell surface. This then acts on adjacent cells. In the nose ATP acts as a nociceptive stimulus which results in anosmia. It is suggested that a similar paracrine mechanism is responsible for the loss of taste. In the lung ATP release from type 2 alveolar cells produces the non-productive cough by acting on purinergic receptors on adjacent neuroepithelial cells and activating, the vagus, the cough reflex. Infection of endothelial cells results in the exocytosis of WeibelPalade bodies. These contain the Von Willebrand Factor responsible for micro-clotting and angiopoietin-2 which increases vascular permeability and plays a key role in the Acute Respiratory Distress Syndrome. To test this hypothesis this paper reports proof of concept studies in which MR blockade using spironolactone and low dose dexamethasone (SpiDex) was given to PCR-confirmed COVID-19 patients. In 80 patients with moderate to severe respiratory failure 40 were given SpiDex and 40 conventional treatment with high dose dexamethasone (HiDex). There was 1 death in the HiDex group and none in the SpiDex. As judged by clinical, biochemical and radiological parameters there were clear statistically significant benefits of SpiDex in comparison to HiDex. A further 20 outpatients with COVID-19 were given SpiDex. There was no control group and the aim was to demonstrate safety. No adverse effects were noted and no patient became hyperkalaemic. 90% were asymptomatic at 10 days. The very positive results suggest that blockade of the MR can produce major benefit in COVID19 patients. Further larger controlled studies of inpatients and outpatients are required not only for SARS-CoV-2 infection per se but also to determine if this treatment affects the incidence of Long COVID.
本文提出，SARS-CoV-2 病毒诱导的三磷酸腺苷（ATP）释放在 COVID-19 的主要症状和并发症的发生中起着关键作用。感染含有血管紧张素转换酶 2（ACE2）受体的特定细胞会导致盐皮质激素受体（MR）失去保护。皮质醇的局部激活刺激 ATP 最初释放到基底外侧隔室，然后通过细胞表面的溶酶体胞吐作用释放。然后，ATP 作用于相邻的细胞。在鼻子中，ATP 作为伤害性刺激物导致嗅觉丧失。有人认为，类似的旁分泌机制负责味觉丧失。在肺部，2 型肺泡细胞释放的 ATP 通过作用于相邻神经上皮细胞上的嘌呤能受体并激活迷走神经，产生非生产性咳嗽反射。内皮细胞感染导致 Weibel-Palade 体的胞吐作用。这些包含 Von Willebrand 因子，负责微凝块形成，以及血管生成素-2，后者增加血管通透性，在急性呼吸窘迫综合征中起关键作用。为了验证这一假设，本文报告了概念验证研究，其中使用螺内酯和低剂量地塞米松（SpiDex）阻断 MR 用于经 PCR 确认的 COVID-19 患者。在 80 名中重度呼吸衰竭患者中，40 名患者接受了 SpiDex 治疗，40 名患者接受了高剂量地塞米松（HiDex）常规治疗。HiDex 组有 1 例死亡，而 SpiDex 组无死亡。根据临床、生化和影像学参数判断，与 HiDex 相比，SpiDex 具有明显的统计学益处。另外 20 名 COVID-19 门诊患者接受了 SpiDex 治疗。没有对照组，目的是证明安全性。未观察到不良反应，也没有患者出现高钾血症。10 天时 90%的患者无症状。非常积极的结果表明，阻断 MR 可以使 COVID19 患者显著受益。需要对住院患者和门诊患者进行更大规模的对照研究，不仅要研究 SARS-CoV-2 感染本身，还要确定这种治疗是否会影响长 COVID 的发生率。
