Therapeutic application of estrogen for COVID-19: Attenuation of SARS-CoV-2 spike protein and IL-6 stimulated, ACE2-dependent NOX2 activation, ROS production and MCP-1 upregulation in endothelial cells

Abstract

The outbreak of COVID-19 has remained uncontained with urgent need for robust therapeutics. 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 less severe disease 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 the 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 IL-6 and S protein-induced selective activation of NADPH oxidase isoform 2 (NOX2), reactive oxygen species (ROS) production, ACE2 upregulation and induction of pro-inflammatory gene monocyte chemoattractant protein-1 (MCP-1) in endothelial cells to effectively attenuate endothelial cell dysfunction. Of note, co-treatment with CSE had no additional effects on S protein stimulated endothelial oxidative stress, again indicating that current smoking status is likely unrelated to more severe disease in chronic smokers. These data indicate that estrogen may 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 severity of the disease and mortality, especially in men. Short-term application of estrogen may therefore be readily used in the clinical management of COVID-19 as a robust therapeutic option.

Cultivation of Cells in a Physiological Plasmax Medium Increases Mitochondrial Respiratory Capacity and Reduces Replication Levels of RNA Viruses

“…This falls in line with the observations from other coronaviruses such as SARS-CoV, as well as other respiratory viral infections [ 61 ]. Other groups reported that SARS-CoV-2 Spike protein up-regulates ROS production in macrophages and endothelial cells upon extracellular treatment [ 63 , 64 ]. A similar effect was described for monocytes, HEK293-ACE and Vero E6 cells infected with the virus or Spike-bearing lentivirus [ 65 , 66 ].…”

Host Factor Interaction Networks Identified by Integrative Bioinformatics Analysis Reveals Therapeutic Implications in COPD Patients With COVID-19

“…Nevertheless, more laboratory and clinical trials are needed before dexamethasone becomes a potential therapeutic drug in the future. In addition, studies have found that 17β-estradiol administration can effectively reduce the up-regulation of ACE2-dependent NOX2, MCP-1 and ROS, and alleviate endothelial dysfunction and multiple organ failure mediated by COVID-19 inflammation during the pathogenesis ( Youn et al, 2021 ). Experiments have pointed out that the combination of progesterone and glucocorticoids can synergistically reduce lung inflammation in mice caused by chronic ozone exposure ( Fei et al, 2017 ).…”

COVID-19 Drug Repurposing: A Network-Based Framework for Exploring Biomedical Literature and Clinical Trials for Possible Treatments

“…Estradiol is one form of estrogen-there are others, too-and may be administered by a number of routes (e.g., by mouth, through the skin). It would not make sense to combine these two drugs together [43][44][45][46][47][48][49]. • Hydroxyethylidene, is etidronic acid, known as a drug its generic name is etidronate and azithromycin (macrolide antibiotic) are possible to combine.…”