Combating Oxidative Stress and Inflammation in COVID-19 by Molecular Hydrogen Therapy: Mechanisms and PerspectivesScientific Research

H2 корона вирус

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

Duried Alwazeer, Tyler W. LeBaron,  Franky Fuh-Ching Liu, Xiao Yu Wu

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.

Conclusion and Perspectives

An explanation for the advantageous effects of molecular hydrogen in COVID-19 treatment is related to the different properties of molecular hydrogen: (1) the small molecular size and nonpolarity of H2 allow it to rapidly permeate the tissues and cells, (2) it can selectively reduce only the cytotoxic ROS, (3) it can suppress the excessive production of otherwise good ROS, (4) it can suppress proinflammatory cytokines, (5) it can induce cytoprotective heat shock proteins, (6) it can improve mitochondrial bioenergetics, and (7) it has no known toxic effects even at very high levels [114]. These properties may explain the improvement in the conditions of COVID-19 patients treated by inhalation of H2/O2 mixed gas (67% H2/33% O2), who felt reduction in chest pain and cough, and easier deeper breathing and comfort sensation [6263]. The positive results of the pilot study led Dr. Zhong Nanshan, the epidemiologist who discovered the SARS virus (SARS-CoV-1) in 2003, to recommend the H2/O2 inhalation therapy for COVID-19 patients [115] and prompted more clinical trials using H2/O2 mixed gas [116118].

Currently, there are twenty registered clinical trials on the use of H2 for COVID-19. Of these, four are registered at the Centre for Evidence-Based Medicine (Oxford) using H2/O2 mixed gas inhalation [116], five clinical trials are registered at of the US National Library of Medicine for inhalation [118], eight clinical trials are registered at ICTRP (WHO) with six for inhalation and two trials for hydrogen-rich water [8], and three clinical trials, related to the use of either inhalation or ingestion of hydrogen-rich water, are registered at the Chinese Clinical Trial Registry center [117]. Up to date, the reported benefits of H2 therapy in COVID-19 patients are limited to the symptomatic description. To expand the utility of H2 therapy in COVID-19, more thorough understanding of the underlying mechanism of H2 in patients is required. Therefore, accurate analysis of a broad spectrum of biomarkers is highly recommended to delineate the correlation between clinical and biochemical presentations and the proposed biological effect of H2.

According to the report of WHO, data from China and around the world suggest that the majority of people with COVID-19 have a mild illness, about 15% of them have a severe illness requiring oxygen therapy, and 5% are critically ill requiring mechanical ventilation. Owing to the widespread transmissibility and emergence of more infectious variants of SARS-CoV-2, many hospitals have been overwhelmed by the crush of new COVID-19 patients and have exhausted ICU beds and ventilators in some regions. Therefore, an alternative yet effective treatment, e.g., H2/O2 gas inhalation, would ease the pressure on hospitals and prevent severe illness of COVID-19 patients.

The medical model of H2/O2 mixed gas machine is small, portable, and safe [119]. It costs about one-tenth of the price of a ventilator. The H2/O2 inhalation treatment may be performed in regular wards or by outpatients at home isolation using a portable H2/O2 generating and inhalation device. This kind of treatment may reduce hospitalization time for a high number of patients. This strategy could decrease the pressure of massive patient numbers on hospitals. It is important to mention that, although molecular hydrogen is not considered a drug, its intake in different ways such as drinking hydrogen-rich water or inhaling H2/O2 gas may be beneficial in preventive medical health in addition to its therapeutic use. Due to the high safety profile and favorable preliminary results in preclinical and clinical studies, application and additional research of molecular hydrogen therapy for COVID-19 are encouraged.