GLUTATHIONE

GLUTATHIONE

Lung inflammation is the main cause of life-threatening respiratory disorders at the severe stage of SARS-CoV-2 infection, characterized by the so-called “cytokine release syndrome (CRS)”. The key to fighting this harmful inflammatory response resides in: (i) addressing the mechanism of the virus penetration into the cell, mediated by binding to and inactivation of the ACE2 protein; (ii) contrasting the exacerbation of the inflammatory response.

The anti-inflammatory effects of reduced glutathione (GSH) are exerted through the inhibition of ACE activity, decrease of reactive oxygen species (ROS) production and reduction of NF-kB activation. The balance ACE/ACE2 is shifted toward ACE by the oxidized form of glutathione (GSSG) and by renin and by viral infection. (Silvagno, 2020).

Endogenous glutathione deficiency appears to be a crucial factor enhancing SARS-CoV-2-induced oxidative damage of the lung and, as a result, leads to serious manifestations, such as acute respiratory distress syndrome, multiorgan failure, and death in COVID-19 patients. Long-term and severe manifestations of COVID-19 infection in one of our patients with marked glutathione deficiency suggest that the degree of glutathione decrease correlates negatively with viral replication rate and that an increasing viral load exacerbates oxidative damage of the lung. This finding suggests that the virus cannot actively replicate at higher levels of cellular glutathione, and therefore, milder clinical symptoms are observed with lower viral loads. (Polonikov, 2020).

The boosted ANGII production can be due to decreased ACE2 expression and activity; this is the case with coronavirus infection, which recognizes ACE2 as its extracellular binding site. Compared to SARS-COV-1, SARS-CoV-2 has about 4-fold higher affinity for ACE2. Infection of cells by SARS viruses that bind ACE2 results in two effects: inhibition of ACE2 activity and decrease of ACE2 expression in infected cells. The increased ANGII, through binding to AT1R, activates NADPH oxidases that transfer an electron from NADPH to O2 generating several radical species, which can be scavenged by GSH. ROS-mediated oxidation can, in turn, alter gene expression through the induction of signaling cascades or the interaction with transcription factors. Among these factors, a prominent role is played by NF-kB, whose role in inflammation in severe acute respiratory syndrome (SARS) has been demonstrated in both SARS-CoV-infected cultured cells and mice [34]. Drugs that inhibit NF-κB activation lead to a reduction in inflammation and lung pathology. NF-kB is involved in inflammation through multiple mechanisms. In vitro, the viral nucleocapsid (N) protein activates interleukin-6 (IL-6) expression through NF-kB binding at the promoter region of the gene. High levels of IL-6 in the acute stage associated with lung lesions were found in SARS patients. By reducing ROS production, GSH inhibits NF-kB activation and consequently keeps the cytokine storm under control. (Silvagno, 2020).

Reference:

(Silvagno, 2020). Silvagno F, Vernone A, Pescarmona GP. The Role of Glutathione in Protecting against the Severe Inflammatory Response Triggered by COVID-19. Antioxidants (Basel). 2020;9(7):624. Published 2020 Jul 16. doi:10.3390/antiox9070624

(Polonikov, 2020). Polonikov A. Endogenous Deficiency of Glutathione as the Most Likely Cause of Serious Manifestations and Death in COVID-19 Patients. ACS Infect Dis. 2020;6(7):1558-1562. doi:10.1021/acsinfecdis.0c00288

(Silvagno, 2020). Silvagno F, Vernone A, Pescarmona GP. The Role of Glutathione in Protecting against the Severe Inflammatory Response Triggered by COVID-19. Antioxidants (Basel). 2020;9(7):624. Published 2020 Jul 16. doi:10.3390/antiox9070624