The COVID-19 pandemic has had a significant impact on global health, particularly for vulnerable populations with pre-existing conditions. Recent research conducted at Northwestern University and Jesse Brown Veterans Affairs Medical Center in Chicago has shed light on the connection between hypercapnia and increased ACE2 expression in bronchial epithelial cells, potentially contributing to poor clinical outcomes in COVID-19 patients with advanced lung disease, hypercapnia, and smokers. The study also suggests that cholesterol-lowering therapies, particularly statins, may offer benefits to individuals with hypercapnia when exposed to or infected with SARS-CoV-2.
Hypercapnia is a condition characterized by elevated levels of carbon dioxide in the bloodstream. When the body’s mechanisms for regulating CO2 levels become compromised, hypercapnia can occur, leading to an accumulation of CO2 in the blood and tissue. This condition can have detrimental effects on overall health and has been found to play a role in influencing the severity of COVID-19.
Individuals with pre-existing health conditions such as chronic obstructive pulmonary diseases (COPD) and smokers are at a higher risk of experiencing severe complications when infected with SARS-CoV-2. The research focuses on the role of ACE2, a receptor for the SARS-CoV-2 spike protein, in the infection process. Previous studies have shown that individuals with comorbidities linked to severe COVID-19 have increased ACE2 expression in the bronchial epithelium, suggesting that this increased expression may enhance viral infection within the airways.
The study demonstrates that hypercapnia elevates ACE2 protein expression in airway epithelium, human bronchial epithelial cells, and VERO cells. This suggests that hypercapnia increases the availability of ACE2 receptors, facilitating greater viral entry into bronchial epithelial cells. The study also explores the relationship between hypercapnia and cholesterol in bronchial epithelial cells, as factors that increase cholesterol content have been found to enhance SARS-CoV-2 infection.
To investigate the influence of hypercapnia on SARS-CoV-2 entry, the research examined pseudo-SARS-CoV-2 infection in epithelial cells. The results showed that elevated CO2 conditions increased the percentage of cells testing positive for pseudo-SARS-CoV-2, indicating an enhancement of viral entry. This effect was consistent with the observed increase in ACE2 protein expression.
The study also delves into the role of cholesterol and lipid rafts, which are crucial platforms for viral entry and assembly, in facilitating SARS-CoV-2 infection. Hypercapnia was found to activate a transcription factor that regulates cholesterol synthesis and transport genes, leading to an increase in cholesterol synthesis and a decrease in cholesterol efflux. This creates a favorable environment for SARS-CoV-2 to enter and infect host cells.
In response to these findings, the study investigates the potential of cholesterol-lowering therapies, particularly statins, to mitigate the effects of hypercapnia on ACE2 expression and SARS-CoV-2 entry. The study found that statins could effectively block the hypercapnia-induced increases in ACE2 expression and viral entry. Statins emerge as a promising avenue for host-directed therapy against viral infections and have already shown potential benefits in preventing severe COVID-19.
The study also explores the effects of cigarette smoke extract (CSE) on ACE2 expression, viral entry, and cholesterol accumulation in bronchial epithelial cells. CSE was found to independently increase ACE2 expression and viral entry through similar cholesterol-dependent mechanisms as hypercapnia. Statins were also effective in mitigating the effects of CSE on bronchial epithelial cells.
These findings highlight the importance of addressing hypercapnia and smoking-related effects on bronchial epithelial cells, potentially through cholesterol-lowering therapies, to reduce the risk and severity of COVID-19 in vulnerable populations. The research provides valuable insights into potential strategies to improve outcomes for individuals with pre-existing conditions and those exposed to harmful environmental factors during the ongoing COVID-19 pandemic.