Hydrogen: A Potential New Adjuvant Therapy for COVID-19 Patients Jul 14, 2021

Hydrogen has been shown to have properties like antioxidant, anti-inflammatory, regulatory hormones, and anti-apoptosis. According to a review of the study, during early COVID-19(coronavirus disease 2019), the use of hydrogen may reduce destructive cytokine storms and lung damage caused by SARS-CoV-2, stimulate viscous sputum drainage, and ultimately reduce the occurrence of serious diseases. Molecular hydrogen therapy has the potential to become a neoadjuvant therapy for COVID-19, but its effectiveness and safety require extensive clinical trials and further validation.

Since novel coronavirus disease (COVID-19) was first reported in Wuhan in late December 2019, it quickly became the sixth largest public health emergency and attracted international attention. As of 11:00 on 31 July 2020,17,328,002 confirmed cases were worldwide, 670,287 deaths, and a total mortality rate of 3.8%. In addition, there were no specific antiviral drugs or vaccines available to prevent COVID-19. Huang found higher plasma IL-2, IL-7, IL-10 and TNF-α concentrations in patients with severe or critical illness than in other patients. This is consistent with Wang shen's pathological results. Therefore, Chen et al. We propose that a cytokine storm is one of the most important factors in critically ill patients. Currently, there are no specific medications available for treating cytokine storms.
Hydrogen, a colorless, odorless, tasteless gas, published a 2007 paper in Nature lining that inhaled 2% hydrogen can selectively remove hydroxyl radicals (OH) and ONOO −), significantly improving cerebral ischemia and reperfusion injury in rats and creating a boom in molecular biology research. Based on hydrogen. The biological effects of hydrogen have been widely studied to date. Based on its biological role in antioxidant, anti-inflammatory, anti-apoptosis, and hormone regulation, hydrogen has been determined to protect it on a variety of diseases. In particular, the small molecular properties of hydrogen ensure it is access to the alveolar quickly, suggesting its unique advantage for lung disease. In view of the current prevalence, on the basis of clinical experience, safety, operability and simplicity, this review discusses the feasibility of hydrogen as a means for the control and prevention of COVID-19 by a clinical generalization.

Hydrogen and cytokine storms
Immune cells can be activated to produce pro-inflammatory cytokines, including tumor necrosis factor- α (TNF-), interleukin (such as IL-1β and IL-6), and interferon- γ (IFN- γ). One role of cytokines is to activate NADPH oxidase in white blood cells resulting in the production of reactive oxygen (ROS) such as superoxides, hydroxyl radicals and monlet oxygen. In 1993, Ferrara et al. The concept of graft resistance against cytokinine storms in host disease was proposed for the first time. The discovery that SARS coronavirus infection induced interferon- γ -related cytokine storms, which may be related to immunopathological lesions observed in SARS patients. In 2005, a study of H5N1 avian influenza A showed that high viral load and the resulting strong inflammatory response were key to its onset. Cytokine storms were also reported in influenza and Middle East Respiratory Syndrome (MERS). The factors causing cytokine storms are currently unknown, but it is widely believed that the immune system overreacts to emerging highly pathogenic pathogens. The associated immunomodulating network imbalance, lack of negative feedback, and positive feedback are continuous self-amplification, leading to an abnormal increase in a variety of cytokes and eventually resulting in a cytokine storm. Although the pathophysiological mechanisms of COVID-19 have not been fully understood, it has been reported that a large number of cytokines in patients with COVID-19, such as IL-1 β, INF-γ, IP-10 and MCP-1,, may activate Th1 cells. Higher concentrations of G-CSF, IP-10, MCP-1, MIP-IA, and TNF-α were found in critical patients than in non-critical patients, suggesting diseases that cytokine storms may be related to the severity of the condition. The effectiveness of anti-IL6 receptor and glucocorticoid therapy in patients with COVID-19 was demonstrated only in a handful of patients. However, more clinical studies on the treatment of COVID-19 with tozumab and dexamethasone are ongoing (NCT04445272, NCT04244591, NCT04381364). Cortical steroids inhibit inflammation in the lungs, but also inhibit immune response and pathogen removal. In addition, the use of antiIL6 receptor therapy in patients with rheumatic diseases may lead to an increased risk of infection. Due to these potential side effects, tozumab and dexamethasone have not yet been widely used in clinical practice.

Excessive cytokines release causes acute lung damage in patients. Increased TNF-α levels will lead to the activation of inflammatory cytokines such as IL-1, IL-6 and IL-8. Meanwhile, the high-mobility families box1 (HMGB1), CCL2, and Egr-1 all affect the release of inflammatory factors. Shekan found that hydrogen inhibited infiltration of neutrophils and macrophages, inhibit activity of NF-κB and MPO in lung tissue, and reduces the secretion of inflammatory and cytokines in lung tissue, including TNF-α, IL-1, IL-6 and HMGB1. Hydrogen can eliminate ROS, such as hydroxyl and peroxide nitrate anions while maintaining the normal metabolism of redox reactions and other ROS s. Thus, hydrogen treatment can reduce the levels of TNF-α, IL-1, IL-1β, IL-6, IL-8, HMGB1, CCL2 and Egr-1 in the animal model lung tissue. In addition, inhalation of hydrogen for 45 minutes reduces airway inflammation in patients with asthma and COPD. Also, previous studies have shown that increased IL-10 can inhibit the synthesis and release of inflammatory cells and colony-stimulating factors. After inhalation of hydrogen, elevated IL-10 was found in the serum and sputum episerum of sanitation workers, indicating that this treatment can affect the anti-inflammatory response and reduce secondary damage caused by cytokine storms. Some patients with severe pneumonia need mechanical ventilation support. However, this causes a lung injury or aggravates the original lung injury. In rat models of mechanical ventilation pulmonary injury, Huang et al. Huang found that expression of NF-κB was activated after 2% hydrogen inhalation, promoted expression of anti-apoptotic protein Bcl-2, inhibited expression of apoptotic protein Bax, inhibited expression of inflammatory factors, reduced lung histopathologic scores, and reduced pulmonary edema, thus reducing ventilator-related acute lung injury. In addition, hydrogen inhibits the Rho/ROCK pathway, increases ZO-1 expression, and protects lung tissue cells by improving intercellular permeability and reducing lung damage. Thus, early use of hydrogen early in COVID-19 patients may inhibit cytokinine release and reduce lung injury.

Hydrogen and oxidative stress reactions in the COVID-19
Superoxide dismutase (SOD) is an important antioxidant enzyme in the body's antioxidant defense system. It removes multiple toxic or oxidative substances in the body, eliminates damage to DNA and functional proteins, maintains the stability of the internal environment, and helps fight toxic and antioxidant processes. After hydrogen treatment, promalaldehyde content in lung tissue decreased and SOD activity increased. This helps to maintain stability in the body's internal environment, achieve overactivation of the oxidation process, and reduce the oxidative stress caused by the ROS pathway. Multiple organ failure is a common cause of death in critically ill COVID-19 patients. Hydrogen can protect multiple organs such as the heart, kidney and nervous system through anti-apoptosis and antioxidant function, maintain the normal response of the body, and reduce mortality.

Hydrogen reduces the viscous secretion associated with COVID-19
According to the pathological anatomy, Liu's team found that in addition to excessive inflammatory reactions, many sticky secretions overflowing from alveand fibers were found in the lung sections, which were mainly concentrated in the terminal bronchial. This is inconsistent with the clinical performance of a dry cough without sputum. Clinical oxygen therapy is mainly assisted by high nasal flow oxygen absorption and non-invasive ventilator ventilation. Therefore, its positive pressure ventilation mode will lead to the accumulation of distal bronchial viscous secretions, increase the airway resistance, change the oxygen effect, and aggravate the systemic hypoxia. This finding suggests new ideas that can be adjusted. Drug atomization and humidification may become an essential treatment means, but in the treatment process, pay attention should be paid to the tertiary protection of medical personnel to prevent aerosol transmission and increase the risk of infection. The mucus is composed of water, ions, lipids, proteins, and complexes. In animal models, airway mucus is found to play an important role in the host defense mechanism, but the production of excess mucus is harmful.  Muc5ac and Muc5b are components of mucin and Muc5ac is produced by cup-shaped cells in airway epithelial cells. In the smoke-induced COPD model, rats treated with hydrogen-rich water have reduced airway damage, Muc5ac expression, and mucus secretion. Therefore, early hydrogen absorption can promote sputum dilution, improve the resistance of the small airway, and relieve breathing difficulties.

Hydrogen safety
According to clinical hydrogen trials, treatment was conducted with hydrogen absorption and drinking hydrogen-rich water. The potential antifatigue and performance advantages of hydrogen-rich water (HRW) over the past five years have attracted increasing research interest. For example, pre-exercise supplementation HRW reduces blood lactic acid at higher exercise intensity, improves the sense of exercise-induced effort, and improves ventilation efficiency. At the same time, hydrogen, as a flammable and explosive small molecular substance, has been clinically developed, and can be safely applied to medical devices. Clinical studies have shown that hydrogen dissolved in the flushing fluid can reduce corneal endothelial damage during phacoemulsification. In addition, breathing H2-O2 may reduce inhalation efforts in patients with acute severe tracheal stenosis and can be safely used for this purpose. Although the H2 gas is flammable, the concentration of <4% is non-combustible along with oxygen at room temperature. As noted in the second law of thermodynamics, although there are multiple possibilities for physical processes satisfying the first law, the only process occurring in nature is where the system entropy remains constant or increases. Thus, the exhaled H2 spreads immediately and does not accumulate or result in an increase in concentration beyond the inspiratory H2 concentration. Therefore, 2% H2gas. can be used in the hospital In this treatment process, a very few patients will appear rare stool, increased defecation times, heartburn, drunk headache and other symptoms. These symptoms may be relieved without intervention. At the same time, these symptoms have no serious adverse reactions and have little harm.

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