The outbreak of COVID-19 has remained uncontained with urgent need for robust therapeutics. We have previously reported sex difference of COVID-19 for the first time indicating male predisposition. Males are more susceptible than females, and more often to develop into severe cases with higher mortality. This predisposition is potentially linked to higher prevalence of cigarette smoking. Nonetheless, we found for the first time that cigarette smoking extract (CSE) had no effect on angiotensin converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) expression in endothelial cells. The otherwise observed worse outcomes in smokers is likely linked to baseline respiratory diseases associated with chronic smoking. Instead, we hypothesized that estrogen mediated protection might underlie lower morbidity, severity and mortality of COVID-19 in females. Of note, endothelial inflammation and barrier dysfunction are major mediators of disease progression, and development of acute respiratory distress syndrome (ARDS) and multi-organ failure in patients with COVID-19. Therefore, we investigated potential protective effects of estrogen on endothelial cells against oxidative stress induced by interleukin-6 (IL-6) and SARS-CoV-2 spike protein (S protein). Indeed, 17β-estradiol completely reversed S protein-induced selective activation of NADPH oxidase isoform 2 (NOX2) and reactive oxygen species (ROS) production that are ACE2-dependent, as well as ACE2 upregulation and induction of pro-inflammatory gene monocyte chemoattractant protein-1 (MCP-1) in endothelial cells to effectively attenuate endothelial dysfunction. Effects of IL-6 on activating NOX2-dependent ROS production and upregulation of MCP-1 were also completely attenuated by 17β-estradiol. Of note, co-treatment with CSE had no additional effects on S protein stimulated endothelial oxidative stress, confirming that current smoking status is likely unrelated to more severe disease in chronic smokers. These data indicate that estrogen can serve as a novel therapy for patients with COVID-19 via inhibition of initial viral responses and attenuation of cytokine storm induced endothelial dysfunction, to substantially alleviate morbidity, severity and mortality of the disease, especially in men and post-menopause women. Short-term administration of estrogen can therefore be readily applied to the clinical management of COVID-19 as a robust therapeutic option.

COVID-19 的爆发仍未得到控制，迫切需要强有力的治疗方法。我们之前首次报告了 COVID-19 的性别差异，表明男性易感性。男性比女性更易感，更容易发展成死亡率更高的重症病例。这种倾向可能与较高的吸烟率有关。尽管如此，我们首次发现吸烟提取物 (CSE) 对血管紧张素转换酶 2 (ACE2) 和跨膜蛋白酶丝氨酸 2 (TMPRSS2) 在内皮细胞中的表达没有影响。在吸烟者中观察到的其他更糟糕的结果可能与慢性吸烟相关的基线呼吸系统疾病有关。相反，我们假设雌激素介导的保护作用可能是降低发病率的基础，女性 COVID-19 的严重程度和死亡率。值得注意的是，内皮炎症和屏障功能障碍是 COVID-19 患者疾病进展、急性呼吸窘迫综合征 (ARDS) 和多器官衰竭发展的主要介质。因此，我们研究了雌激素对内皮细胞对抗白介素 6 (IL-6) 和 SARS-CoV-2 刺突蛋白（S 蛋白）诱导的氧化应激的潜在保护作用。事实上，17β-雌二醇完全逆转了 S 蛋白诱导的 NADPH 氧化酶同种型 2 (NOX2) 的选择性激活和 ACE2 依赖性活性氧 (ROS) 的产生，以及 ACE2 上调和促炎基因单核细胞趋化蛋白的诱导-1 (MCP-1) 在内皮细胞中有效减轻内皮功能障碍。IL-6 对激活 NOX2 依赖性 ROS 产生和 MCP-1 上调的影响也被 17β-雌二醇完全减弱。值得注意的是，与 CSE 联合治疗对 S 蛋白刺激的内皮氧化应激没有额外影响，证实目前的吸烟状况可能与慢性吸烟者更严重的疾病无关。这些数据表明，雌激素可以通过抑制初始病毒反应和减弱细胞因子风暴引起的内皮功能障碍，作为 COVID-19 患者的一种新疗法，从而显着降低该病的发病率、严重程度和死亡率，尤其是在男性和后遗症患者中。更年期妇女。因此，短期服用雌激素可以很容易地应用于 COVID-19 的临床管理，作为一种强有力的治疗选择。