Combating Oxidative Stress and Inflammation in COVID‐19 by Molecular Hydrogen Therapy: Mechanisms and Perspectives

Abstract

COVID-19 is a widespread global pandemic with nearly 185 million confirmed cases and about four million deaths. It is caused by an infection with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which primarily affects the alveolar type II pneumocytes. The infection induces pathological responses including increased inflammation, oxidative stress, and apoptosis. This situation results in impaired gas exchange, hypoxia, and other sequelae that lead to multisystem organ failure and death. As summarized in this article, many interventions and therapeutics have been proposed and investigated to combat the viral infection-induced inflammation and oxidative stress that contributes to the etiology and pathogenesis of COVID-19. However, these methods have not significantly improved treatment outcomes. This may partly be attributable to their inability at restoring redox and inflammatory homeostasis, for which molecular hydrogen (H2), an emerging novel medical gas, may complement. Herein, we systematically review the antioxidative, anti-inflammatory, and antiapoptotic mechanisms of H2. Its small molecular size and nonpolarity allow H2 to rapidly diffuse through cell membranes and penetrate cellular organelles. H2 has been demonstrated to suppress NF-κB inflammatory signaling and induce the Nrf2/Keap1 antioxidant pathway, as well as to improve mitochondrial function and enhance cellular bioenergetics. Many preclinical and clinical studies have demonstrated the beneficial effects of H2 in varying diseases, including COVID-19. However, the exact mechanisms, primary modes of action, and its true clinical effects remain to be delineated and verified. Accordingly, additional mechanistic and clinical research into this novel medical gas to combat COVID-19 complications is warranted.

Molecular hydrogen as an adjuvant therapy may be associated with increased oxygen saturation and improved exercise tolerance in a COVID‐19 patient

“…Although the exact molecular mechanism of how hydrogen therapy provides benefits to COVID‐19 patients is not known, several mechanisms have previously been suggested. 7 , 8 , 9 , 10 , 11 , 12 …”

“…Although the exact molecular mechanism of how hydrogen therapy provides benefits to COVID-19 patients is not known, several mechanisms have previously been suggested. [7][8][9][10][11][12] Fatigue remains a common reported side effect of acute COVID-19, with chronic fatigue being reported as one of the most common side effects of post-acute COVID-19. 30 HRW as delivered by hydrogen-producing magnesium tablets has shown to improve alertness equivalent to caffeine in a head-to-head crossover study in young, healthy, sleep-deprived individuals (n = 23).…”

“… 1 , 7 , 8 , 9 It is hypothesized that H 2 therapy may decrease inflammation by decreasing the cytokine storm and by reducing free radical‐induced damage, which may decrease hypoxia and delay the need for oxygen therapy. 7 , 8 , 9 , 10 , 11 , 12 This hypothesis has led to the initiation of a large‐scale multicenter trial in Europe utilizing hydrogen‐producing tablets in high‐risk patients undergoing ambulatory care. 13 The concept that molecular hydrogen may be a beneficial treatment for severe COVID‐19 is supported by a small trial in China that reported hydrogen inhalation was effective for reducing disease severity and dyspnea.…”

“…6 Recently, molecular hydrogen (H 2 ) has been suggested for the treatment of COVID-19, due to its potential antioxidant and anti-inflammatory effects. 1,[7][8][9] It is hypothesized that H 2 therapy may decrease inflammation by decreasing the cytokine storm and by reducing free radical-induced damage, which may decrease hypoxia and delay the need for oxygen therapy. [7][8][9][10][11][12] This hypothesis has led to the initiation of a large-scale multicenter trial in Europe utilizing hydrogen-producing tablets in high-risk patients undergoing ambulatory care.…”

Hydrogen, a Novel Therapeutic Molecule, Regulates Oxidative Stress, Inflammation, and Apoptosis

“…Mitochondrial ROS production usually occurs in the early stage of cell injury, which can lead to destruction of the cell membrane of the alveolar epithelial cells and inactivation of surfactant, thus increasing membrane permeability, leading to increased leakage of proteins into the alveoli during lung injury (Alwazeer et al, 2021 ). Yet despite high-speed oxygen ventilation, inflammation of the respiratory tract and exudation of viscous mucus in bronchioles and alveoli make oxygenation of blood inefficient in severe COVID-19 as O 2 cannot easily penetrate mucus plugs.…”