Hydrogen therapy as an effective and novel adjuvant treatment against COVID-19

We read with great interest the recent article by Wang et al.,which showed that 45 min hydrogen gas (XEN) inhalation once attenuated airway inflammation in asthma and chronic obstructive pulmonary disease (COPD) patients by mainly inhibiting the pro-inflammatory cytokines of monocyte chemoattractant protein-1 (MCP-1), interleukin-4 (IL-4) and IL-6. High IL-6 level had also been found closely correlated with the incidence of detectable serum severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load and the vital signs of coronavirus disease 2019 (COVID-19) patients.As of 14 September 2020, 28 637 952 confirmed cases of COVID-19 patients have been reported with 917 417 deaths in 212 countries globally,and COVID-19 has caused an unprecedented global public health crisis.However, to date, effective therapeutic approach or antiviral drugs for COVID-19 remain limited.

Hydrogen (H₂) is colorless, odorless and the lightest of gas molecules in the universe. Since the first reported hydrogen therapy in a skin squamous carcinoma mouse model, studies in the past 10 years have indicated that H₂ has therapeutic effects in diverse animal models and human disease, including metabolic syndrome, organ injury (respiratory system, nervous system, reproductive system, etc.), radiation damage and cancer, from acute illness to chronic illness. We hypothesize that hydrogen therapy may be as an effective and novel adjuvant treatment against COVID-19, and exhibit the beneficial potential to prevent COVID-19-associated cytokine storm and multiple organ damage through following multiple mechanisms.First, H₂, as an important physiological regulatory factor with antioxidant effects on cells and organs, could activate the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, provide cytoprotective activity and reduce tissue damage caused by SARS-CoV-2 infection.Additionally, oxidative stress induced by viral infections could exacerbate the DNA methylation defect which may result in further angiotensin-converting enzyme 2 (ACE2, a functional receptor for the viral spike glycoprotein that allows the entry of SARS-CoV-2 into cells) hypomethylation and enhanced viremia.H₂, as an antioxidant,may downregulate ACE2 expression through epigenetic control of the ACE2 gene. Second, SARS-CoV-2 induced activation of apoptosis and protein 53 (p53) signaling pathway in lymphocytes may play an important role in the development of patients’ lymphopenia,while H₂ could exert anti-apoptotic effects in lymphocytes attributed to its free radicals scavenging capacity, which may prevent disease progression and be used for prevention and treatment in COVID-19 patients.Last, but definitely not least, H₂ can suppress proinflammatory gene expression (tumor necrosis factor-α, IL-1β, IL-6, IL-10 and intercellular cell adhesion molecule-1) via nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κb) pathway, while these pro-inflammatory cytokines could be overexpressed in COVID-19 infection and play important roles in the progress of diseases.

In conclusion, with the effects on selective anti-oxidation, anti-apoptosis, anti-inflammation, gene expression alterations and as a gaseous signal modulator, hydrogen therapy may be a novel, promising and effective adjuvant treatment against COVID-19. Although additional experiments and clinical studies are required to confirm this hypothesis, we hope that hydrogen therapy would provide an emerging and good option for the currently limited prevention and treatment strategy of COVID-19.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflict of interest. None declared.

Ethical statement: The article does not contain the participation of any human being and animal.

Verification: All authors have seen the manuscript and agree to the content. All the authors played a significant role in the paper