The Role of Glutathione in Protecting against the Severe Inflammatory Response Triggered by COVID-19

The Role of Glutathione in Protecting against the Severe Inflammatory Response Triggered by COVID-19

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402141/

Antioxidants (Basel). 2020 Jul; 9(7): 624.

Published online 2020 Jul 16. doi: 10.3390/antiox9070624

PMCID: PMC7402141

PMID: 32708578

Francesca Silvagno,* Annamaria Vernone, and Gian Piero Pescarmona

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Abstract

The novel COVID-19 pandemic is affecting the world’s population differently: mostly in the presence of conditions such as aging, diabetes and hypertension the virus triggers a lethal cytokine storm and patients die from acute respiratory distress syndrome, whereas in many cases the disease has a mild or even asymptomatic progression. A common denominator in all conditions associated with COVID-19 appears to be the impaired redox homeostasis responsible for reactive oxygen species (ROS) accumulation; therefore, levels of glutathione (GSH), the key anti-oxidant guardian in all tissues, could be critical in extinguishing the exacerbated inflammation that triggers organ failure in COVID-19. The present review provides a biochemical investigation of the mechanisms leading to deadly inflammation in severe COVID-19, counterbalanced by GSH. The pathways competing for GSH are described to illustrate the events concurring to cause a depletion of endogenous GSH stocks. Drawing on evidence from literature that demonstrates the reduced levels of GSH in the main conditions clinically associated with severe disease, we highlight the relevance of restoring GSH levels in the attempt to protect the most vulnerable subjects from severe symptoms of COVID-19. Finally, we discuss the current data about the feasibility of increasing GSH levels, which could be used to prevent and subdue the disease.

Keywords: SARS-CoV-2, angiotensin-converting enzyme (ACE), angiotensin-converting enzyme 2 (ACE2), glutathione, inflammation, ROS, N-acetylcysteine, glycine, chloroquine, paracetamol

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1. Introduction

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 standard pharmacological approach would suggest either the use of an antiviral drug with the aim of blocking viral replication or the exploitation of drugs previously validated as inhibitors of some inflammatory pathway in other chronic diseases. Unfortunately, these drugs are ineffective in healing the most severe cases of SARS-CoV-2, and additionally, they have several side effects. The baffling aspect of this disease is the great heterogeneity of response among patients, ranging from severe symptoms to asymptomatic progression. Understanding the protective mechanisms and the reasons of their failure could provide a breakthrough in the quest for a cure.

The inflammatory response can be traced back to the pathway of viral entry through its receptor ACE2. Angiotensin-converting enzyme 2 (ACE2) is a protease that, with its companion the angiotensin-converting enzyme ACE, takes part in the renin-angiotensin system (RAS). They are localized at the cell surface and compete for the same substrates, angiotensin I and II. ACE2 counters the activity of ACE by reducing the amount of angiotensin-II (ANGII) and increasing ang (1-7) peptide. The downstream effects of the two enzymes are opposite: ACE activity leads to vasoconstriction, oxidative stress, inflammation and apoptosis, whereas ACE2 causes vasodilatation, angiogenesis and anti-inflammatory, anti-oxidative and anti-apoptotic effects [1]. The oxidative stress generated by ACE activity is due to the effects of its product, ANGII, which increases the production of reactive oxygen species (ROS) through the activation of NADPH oxidase and the generation of peroxynitrite anions. In contrast, the ang (1-7) peptide synthesized by ACE2 activity leads to a downregulation of pro-oxidant pathways, which prevents or attenuates the cellular damage induced by oxidative stress.

Each person has a different balance between ACE and ACE2 and can be more prone to inflammation if ACE prevails. When this happens, and additionally infection by SARS-CoV-2 downregulates ACE2 abundance on cell surfaces, as suggested by evidence from related coronaviruses [2], the result is the toxic overaccumulation of ANGII, exacerbated inflammation and, finally, acute respiratory distress syndrome and fulminant myocarditis (Figure 1). A different balance of ACE/ACE2 can explain the heterogeneous responses to infection caused by the same virus. The link between the dysregulation of the RAS cascade and the likelihood or severity of SARS-CoV-2 infection has been discussed in some recent works [3,4], and it is a matter of importance when the effects of the RAS inhibitors are debated [5].

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