Potential Therapeutic Targets of Hydrogen for Treating COVID-19

Coronavirus Disease 2019 (COVID-19) caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has led to the ongoing global pandemic. The pathophysiological process of COVID-19 is an excessive inflammatory response in the host after virus infection.

Study: Molecular Hydrogen: A Promising Add-On Strategy To Treat COVID-19. Image source: ker_vii / Shutterstock

Several therapies have been tested to alleviate the symptoms of this disease; however, there is no specific and effective treatment. Hydrogen therapy has been included in a new treatment plan for COVID-19 in China.

An article recently published in Frontiers in Medicine provided an overview of a study led by academic Zhong Nanshan in China on COVID-19 treatment by inhaling a mixed gas of hydrogen and oxygen.

This article also describes the pathophysiology of COVID-19, summarizes the therapeutic effects and underlying mechanisms of hydrogen in critical disease, and analyzes the feasibility and potential therapeutic goals of hydrogen in the treatment of COVID-19.

Mechanisms of COVID-19

In COVID-19, the excessive activation of immune cells and the persistent inflammation caused by the viral infection create large amounts of reactive oxygen species (ROS). After a SARS-CoV-2 infection, its replication depends on the energy metabolism of the host cells, while the glycolytic pathway of the host cells is significantly enhanced, which leads to the production of large numbers of ROS.

In the course of COVID-19, the effects of SARS-CoV-2 infections and ROS produced by the two pathways mentioned above lead to diffuse alveolar damage. This hinders alveolar gas exchange and causes dyspnoea and hypoxemia. As a result, the lungs are more prone to secondary infections.

Hydrogen therapy

Hydrogen therapy targets both inflammatory storms and ROS. Hydrogen, the known gas with the lowest density, has the smallest molecular mass and a certain degree of reducibility. Previously, hydrogen therapy was used for UV-induced squamous cell carcinoma, end-stage colon cancer, parasitic liver disease, cerebral ischemia-reperfusion damage, Parkinson’s disease, soft tissue injuries, insulin resistance, rheumatoid arthritis, tumors, sepsis, and organ injuries. Hydrogen therapy has been shown to be effective in treating inflammatory damage.

The hydrogen used in clinical studies was initially mainly in non-gaseous form. Clinical studies have shown that drinking hydrogen-rich water (HRW) is safe and well tolerated; HRW with 7 ppm H2 could protect the vascular endothelium from ROS.

Other forms of hydrogen that have been used include – injection of hydrogen-rich saline solution containing 1ppm H2, hydrogen-rich tablets, and hydrogen-rich capsules for oral use.

Recently, clinical studies have also confirmed the therapeutic effects of hydrogen gas inhalation. Therapeutic effects of inhalation of hydrogen gas have been demonstrated in patients with acute severe tracheal stenosis, end-stage colorectal cancer, acute cerebral infarction, postcard arrest syndrome after acute myocardial infarction, and non-small cell lung cancer. However, there is a lack of evidence of a direct effect of hydrogen on viruses.

Currently, COVID-19 hydrogen therapy involves inhaling a mixture of hydrogen and oxygen (66% hydrogen; 33% oxygen) at 6 l / min through the nasal cannula using a hydrogen / oxygen generator. There is evidence that standard-of-care H2-O2 inhalation for 7.7 hours significantly improved COVID-19 severity within two days, including the dyspnoea scale, chest pain, chest pain, cough scale, and resting oxygen saturation Compared to the control group of patients who received standard daily care of oxygen therapy.

These advantages are likely conferred by the lower resistance to inhalation after inhalation of a hydrogen / oxygen mixture. In another case, a multicentre, randomized, double-blind, controlled, parallel-group study showed that inhalation of a hydrogen-oxygen mixture was better than just oxygen therapy, in acute exacerbation of symptoms of chronic obstructive pulmonary disease (COPD), including dyspnoea, cough and sputum. with an acceptable safety and tolerability profile.

Potential targets of hydrogen in COVID-19

Neutrophils

It has been found that inhalation of hydrogen gas can decrease the infiltration of neutrophils into the lung tissue and help in alleviating inflammatory damage to the lung tissue in the disease states.

There is evidence that inhalation of hydrogen gas improved structural lung damage induced by inflammatory cell infiltration and increased survival in heavy septic mice modeled with appendix ligation and perforation.

In addition, in a rat model of hemorrhagic shock and resuscitation, brief inhalation of 2% hydrogen gas after hemorrhagic shock and resuscitation minimized the degree of lung injury by reducing the infiltration of inflammatory cells into the lung tissue.

Macrophages

Hydrogen reduces monocyte adsorption by the endothelial adhesion molecules in an inflammatory response, thereby preventing blood-borne monocytes from passing through the vascular endothelium and being activated into the macrophages that cause an excessive inflammatory response. Hydrogen therapy can stabilize the function of macrophages and prevent damage from excessive activation and phagocytic defects.

Cytokines

Hydrogen reduces inflammation of the airways by lowering cytokine levels. The use of hydrogen gas can reduce the destructive cytokine storm and lung injury caused by SARS-CoV-2 in the early stages of COVID-19 and stimulate sputum drainage and ultimately reduce the incidence of serious illness.

Reactive oxygen species

In COVID-19, ROS and inflammatory response can be codependent. Hydrogen can either work by directly removing toxic ROS or indirectly improving the body’s antioxidant activity. Hydrogen therapy has both anti-inflammatory and antioxidant effects, so it can help prevent the disease from progressing in COVID-19.

Additional therapy

The main reason for COVID-19-related respiratory diseases is that SARS-CoV-2 attacks the endothelial cells of the pulmonary capillaries and triggers an immune response. Hydrogen therapy can inhibit tissue damage by the inflammatory cells at all stages of the inflammatory response.

Despite its potential effectiveness and safety for use as add-on therapy, the mechanism by which hydrogen relieves symptoms in patients with COVID-19 needs further clarification

Journal reference:

• Li, Y., Wang, Z., Lian, N., Wang, Y., et al. (2021) “Molecular Hydrogen: A Promising Add-on Strategy for Treating COVID-19,” Frontiers In Medicine, doi: 10.3389 / fmed.2021.671215 https://www.frontiersin.org/articles/10.3389/fmed.2021.671215/full