Molecular hydrogen and its role in COVID-19 management

Hydrogen gas has been used against many diseases and is considered a safe and reliable treatment with little or no adverse effects. In this article, we will explore the health benefits and action mechanisms of hydrogen gas in COVID-19 patients manifesting lung damage and other related complication.

Molecular Hydrogen and Its Biological Effects

Molecular hydrogen is the smallest inert gas, having no color, odor, or taste. Moreover, it is non-toxic and poorly soluble in water (1, 2). It is added as an essential constituent in the gas cylinders of deep-sea divers to help them breathe properly and prevent nitrogen decompression and illness (3). The therapeutic potential of hydrogen gas was first assessed by Dole et al. They studied that hyperbaric hydrogen could repress skin cancer in mice models after two weeks of treatment. However, later the application of hyperbaric hydrogen was restricted due to its transportation, storage and administration issues (4). Afterward in 2007, the use of low concentration of molecular hydrogen gas was proposed as a beneficial treatment in inflammation and ischemia/reperfusion animal models, considering its antioxidant and anti-inflammatory properties (5). Besides these, hydrogen also exerts anti-fatigue, anti-apoptosis, and regulatory effects. Molecular hydrogen can be administered in a number of ways i.e., hydrogen gas inhalation, hydrogen-rich saline and hydrogen-rich water (6). Hydrogen gas therapy has shown beneficial health effects in a variety of diseases, thus, it has also been proposed as a promising therapy for COVID-19 patients (7).

In this article, we will explore the therapeutic potential of molecular hydrogen in the management of COVID-19 infection. However, before heading toward COVID-19 disease, let’s first understand the mechanism of hydrogen gas in ameliorating experimental lung damage and complications.

Effects of Hydrogen gas inhalation on Experimental Lung Damage

To understand the action mechanism of molecular hydrogen in lung damage improvement, several in vivo studies have been done. In these investigations, lung damage is introduced through experimental means to develop disease models. These models provide a convenient and reliable source for screening different treatment regimens. Different pathological processes such as acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) initiate in the lungs due to extreme, non-specific inflammation, which causes direct or indirect damage to lung tissues, including alveolar structures (8). Hydrogen gas has the ability to ameliorate lung damage effectively by using its antioxidant and anti-inflammatory characteristics. Such as hydrogen gas inhalation is reported to attenuate experimentally induced lung fibrosis by repressing oxidative stress and inflammation. Molecular hydrogen exerts these positive effects by inhibiting transforming growth factor (TGF-β1) and epithelial-to-mesenchymal transition (9). Similarly, hydrogen inhalation has proved to be an effective regimen against bleomycin-induced alveolar fibrosis that decreases respiratory physiological function. In this study, repeated hydrogen inhalation therapy was carried out for 21 days with 3.2% molecular hydrogen gas for six hours per day. The treatment increased ventilation and alveolar compliance which suggests it is a safe and effective therapy to ameliorate the clinical profile of patients with acute respiratory distress syndrome (10). Furthermore, safe concentrations of hydrogen gas can also mitigate ventilator induce lung damage in experimental mice models. It shows strong anti-inflammatory, anti-apoptotic and antioxidant effects in treating the condition. Mainly, hydrogen decreases ventilation-induced epithelial cell death by increasing the expression levels of anti-apoptotic genes. Additionally, adjunctive therapy with hydrogen gas inhalation is effective and appropriate for lung disease. Moreover, it is a straightforward and easily delivered therapeutic approach. (11). Moving forward, molecular hydrogen is found protective against hypoxia /re-oxygenation (H/R) injury to the lungs. It works by suppressing systemic and pulmonary inflammatory reactions and declining the production of hydroxyl radicals massively generated during H/R-induced lung damage (12). Like H/R, hemorrhagic shock and resuscitation (HSR) are known to initiate inflammatory responses in lung tissue causing acute lung injury and upsurging the risk of problems that can lead to death. Inhalation of hydrogen gas at 2% concentration is reported to minimize the rate of lung damage after HSR in a rat model. It reduces myeloperoxidase (MPO) activity, a pro-inflammatory molecule, and decreases the inflammatory cells’ infiltration to damaged lung tissue (13). These findings suggest that hydrogen gas has the ability to combat oxidative stress and inflammation, and regulate cellular machinery to exert a protective effect against lung tissue damage. Thus, it can also be a promising therapeutic option against the deadly coronavirus disease (COVID-19) and related lung injury and health complications.Considering these beneficial effects of hydrogen gas therapy in lung injury, we can suggest its use for combating COVID-19 infection.

Role of molecular hydrogen in Coronavirus disease (COVID-19) management

COVID-19 is a highly infectious and deadly disease caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus (2). It has exerted a disastrous effect on the world’s demographics and resulted in more than six million deaths worldwide, thus evolving as the most significant global health crisis (14). Most of the COVID-19 cases demonstrate a respiratory disease with unclear symptoms. It starts with a fever, fatigue, and dry cough and is trailed by shortness of breath (dyspnea) with the deteriorating disease. Among all patients, 80% may recover without any need for hospitalization, however, the rest 20% may develop pneumonia and severe acute respiratory distress syndrome (ARDS) (15). This indicates that the COVID-19 infection may range from silent to severe disease, involving death. The SARS-CoV-2 disease is also linked with the consolidation of the upper and lower lungs that causes respiratory breakdown along with hypoxia (lack of oxygen). Lung consolidation is meant by filling small airways in the lungs with water, blood, or pus rather than air (16, 17). Furthermore, fatigue, joint pain, headache, dyspnea, and lung, heart, and neurological damage are reported as long-term effects of coronavirus disease-19 (18).

Oxidative stress and ROS production during COVID-19 infection

Viral infections such as COVID-19 disease is associated with the infiltration of neutrophils and the production of reactive oxygen species (ROS). In addition to this, it also influences the antioxidant defenses of the body. Excessive ROS levels initiate a series of biological processes that lead to pathological host responses. Therefore, ROS significantly promotes coronavirus disease severity by inducing inflammatory responses, tissue damage, red blood cell dysfunction, thrombosis, etc. Thus, radical scavengers such as hydrogen gas can help most susceptible COVID-19 patients (7, 19). Molecular hydrogen possesses favorable attributes, intrinsic biosafety, and high affinity that characterize its therapeutic capacity and makes it a suitable treatment option (6).  Hydrogen gas may reduce inflammation by relieving cytokine storm and suppressing free radicals-mediated lung tissue damage, which alleviates hypoxia condition and lags the demand for oxygen therapy (20). Further, alveolar macrophages, hypoxia, and ROS result in inflammatory responses that may lead to acute respiratory distress syndrome. Additionally, excessive production of proinflammatory cytokines may also harm multiple organs. Herein, hydrogen gas inhalation may provide an efficient solution to combat oxidative stress and hypoxia and reduce downstream production of cytokines to prevent and deal with cytokine storm in COVID-19 (15).

Studies on hydrogen inhalation therapy in COVID-19 disease

Hydrogen gas is found to regulate a variety of cellular pathways to exert its antioxidant and anti-inflammatory effects in the management of chronic inflammatory lung diseases. Therefore, it is proposed as an effective therapy to relieve pulmonary symptoms of coronavirus disease-19 (21). Considering these positive effects, hydrogen gas was directly administered in patients despite limited research studies at the start of the pandemic to save people’s life.  Studies have shown that molecular hydrogen can inhibit lung damage and harmful cytokine storm caused by the SARS CoV-2 virus in the early stage of the disease. Thus, it encourages sputum drainage and prevents the worsening of COVID-19 disease (22). Hydrogen inhalation therapy may also restrict COVID-19 disease progression and ameliorate airway resistance, and effectively help treat COVID-19 infection (23). Furthermore, molecular hydrogen therapy has shown beneficial effects and improved the life expectancy of severely ill COVID-19 patients admitted to the intensive care unit (ICU). COVID-19 patients with severe hypoxemia were administered hydrogen gas for at least one week until their condition is sufficiently improved. In China, a national class III medical device containing a hydrogen-oxygen mixture was developed and used for COVID-19-related pneumonia patients. The device was reported to have certain beneficial effects on the improvement of hypoxic symptoms. New treatments can be devised to save the lives of severe COVID-19 patients (24). Hydrogen is also administered as oxy-hydrogen gas which is a mixture of molecular oxygen and molecular hydrogen gases produced by the electrolysis of water. It is delivered in 2:1 concentration by using inhalation devices, including nebulizers or nasal cannulas. Investigations exhibited that oxy-hydrogen gas exerts protective effects by eliminating oxidative stress and reducing inflammatory responses. As inflammation is the main trigger of many pathologies, including chronic obstructive pulmonary disorder, asthma, and SARS coronavirus disease (COVID-19). Additionally, direct delivery to lung tissues can enhance the outcomes of this emerging therapy (25). Besides the COVID-19 infection treatment and related complications, hydrogen gas inhalation therapy has been shown to offer beneficial health effects post-COVID-19 disease. A study exhibited improvement of the respiratory and physical function in patients who were administered hydrogen gas post-SARS CoV-2 disease (26).

All these studies have suggested hydrogen inhalation therapy as a promising and efficient adjuvant therapy against COVID-19-positive patients due to its effect on selective anti-inflammatory, antioxidant, anti-apoptotic, and gene expression alterations. However, additional experimental and clinical investigations are required to validate its use in clinical settings (27). Moreover, further studies can help hydrogen therapy to improve and emerge as a good treatment option for the deadly COVID-19 disease.

Clinical Use of Hydrogen Inhalation therapy for the treatment of COVID-19

After the emergence of COVID-19 infection, many therapies were proposed to combat disease outcomes. However, many of these solutions were associated with mild to severe side effects, thus not being administered in a clinical setup. Contrary to this, hydrogen gas therapy was proposed in the early pandemic and also used for the treatment of SARS CoV-2 infection as discussed above.

Many clinical studies on the use of molecular hydrogen were carried out in COVID-19 patients. Such a retrospective study was conducted in China in which 12 patients hospitalized with COVID-19 infection were included. The patients were given routine therapy as well as additional hydrogen-oxygen treatment. The treatment group showed a considerable decline in neutrophil percentage and an anomalous proportion of C-reactive protein (CRP). Further, oxygen-hydrogen therapy relieves clinical symptoms of coronavirus patients by reducing inflammatory responses (28). Similar to this, the hydrogen/oxygen mixed gas inhalation was clinically administered in patients manifesting dyspnea or shortness of breath related to COVID-19 infection. This pilot scale open-label clinical study showed significant amelioration of dyspnea in patients after treatment and suggested Hydrogen/oxygen gas inhalation therapy safe for patients (29).

Another interesting clinical study investigated the effect of hydrogen inhalation in post-COVID-19 patients. They evaluated the physical and respiratory function through 6 min walk and pulmonary function test in COVID-19 patients after 21 and 33 days of positive lab tests. The treatment group was administered hydrogen gas for two hours a day for 14 days. The therapy showed beneficial effects on patients and improved their physical and respiratory functions significantly. Therefore, hydrogen inhalation represents a safe treatment strategy that may speed up post-COVID-19 rehabilitation (30). Further, an interesting study utilized hydrogen inhalation therapy in the rehabilitation program of a hospital’s medical staff recovered from coronavirus disease. The study indicated that hydrogen therapy decreased endothelial dysfunction and silent hypoxia features in patients. However, it increased exercise tolerance and physical function. Thus, suggested hydrogen gas as a highly effective and safe treatment method for proper recovery of post-COVID-19 patients (31).

These clinical pieces of evidence are still not enough and comprehensive to officially label hydrogen gas inhalation as anti-COVID-19 therapy. Therefore, more clinical studies including a larger sample size should be designed to evaluate the treatment effectiveness and safety. This will help in developing a cheap and reliable SARS-CoV-2 infection treatment in the near future, ensuring the patient’s well-being.

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