Combating Oxidative Stress and Inflammation in COVID-19 by Molecular Hydrogen Therapy: Mechanisms and Perspectives
Although hydrogen-oxygen inhalation therapy is ?simple?, it can protect life, this is it?s? greatness?.
Kecheng Xu, MD
WHAT IS COVID-19
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 (Lung air sacks) type II pneumocytes. The infection causes specific conditions in the body responses including increased inflammation, oxidative stress, and apoptosis. (Cell death) This situation results in impaired gas exchange, hypoxia, and other sequelae that lead to multisystem organ failure and death.
Acute lung injury (ALI) can be caused by a variety of factors, such as hyperoxia, mechanical ventilation, sepsis, multiple traumas, cardiopulmonary bypass, and viral pneumonia which causes acute respiratory failure and systemic inflammation presented by hypoxemia, lung infiltration, and edema. Oxidative stress, inflammation, and mitochondrial dysfunction play crucial roles in the pathogenesis of ALI [Fan, et al., 2018; Chalmers, et al., 2019].
How and why does the inhalation of Hydrogen gas impact Cytokine Storms, runaway oxidative stress, rampant inflammation and the prevention as well as the regression of fibrosis
A short video presentation courtesy of MHI presented by Tyler W. LeBaron (founder and CEO) [M.Sc Sport and B.Sc Biochemistry]
Pathogenesis of Viral Infectious Lung Diseases
Among human coronaviruses (HCoVs), the severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV) together with COVID-19 pose huge threats to global public health [Liu, et al., 2020]. They are polycistronic positive-strand RNA viruses, containing a genome of about 30 kb, encoding a variety of non-structural proteins (ORF1a and ORF1b) and a number of specific auxiliary proteins (such as ORF3a, ORF3b, ORF6, ORF7a, ORF7b ORF8a, ORF8b, and ORF9b) [Kannan, et al., 2020]. The genomic sequences of the three coronaviruses are highly identical and highly pathogenic. In the pathogenesis, especially in the case of acute respiratory failure, the following mechanisms work: cytokine storm, apoptosis and necrosis, immunopathology, and fibrosis. The activation of all four might be related to oxidative stress.
Oxidative Stress and ROS During Viral Respiratory Infections plays a fundamental role in the degenerative process in the infected persons reparatory processes and abilities.
Oxidative stress is an imbalance between oxidants and ntioxidants in favour of the oxidants, leading to a disruption of redox signalling and control and/or molecular damage [Sies, 2015]. Reactive oxygen species (ROS) is main cause of oxidative stress. Virus-induced oxidative stress plays a critical role in the viral life cycle as well as the pathogenesis of viral injury. Also, in response to ROS generation by a virus, a host cell activates an antioxidative defence system for its own protection.
ROS production during respiratory viral infections;
Studies on HCoVs infections have demonstrated that pneumonia, lymphopenia, and inflammatory cell infiltration are parallel to the production of ROS, which is considered to be the primary pathogenic molecules of viral lung injury [Vlahos, et al., 2012]. There are several studies which show that oxidative stress plays an important role in the pathogenesis and development of viral infections [Khomich,
et al., 2018].
Other respiratory viruses also promote the production of ROS. Human respiratory syncytial virus (HRSV) [Casola, et al., 2001] and Sendai virus (SeV) [Gao, et al., 2016; Qian, et al., 2019] trigger an increase in total ROS levels in airway cells. Lin, et al. [2016] demonstrated that acute lung injury caused by H5N1 infection is due to excessive ROS production which may trigger oxidized phospholipid signalling and cause acute lung injury.
Production of ROS in airway epithelial cells infected with influenza virus or
human respiratory syncytial virus (HRSV) and rhinovirus.
The sources are mainly represented by nicotinamide adenine dinucleotide phosphate
oxidases (NADPH oxidases, NOx), Dual oxidase (Duox) and xanthine oxidase (XO).
XO: xanthine oxidase; ETC: electron transport chain.
Modified from Khomich, et al. [2018].
Obstructive pulmonary disease model
There is an increasing number of studies suggesting the role of oxidative stress in the development and progression of chronic obstructive pulmonary disease (COPD). There are two experimental studies on the improvement of COPD by hydrogen-oxygen inhalation. The first study was completed by the respiratory disease team of the First Affiliated Hospital of Guangzhou Medical University [Lu, et al., 2018]. It is as follows:
A COPD mouse model was established in male C57BL mice by cigarette smoke (CS) exposure. For H2 treatment, after exposure to CS for 60 days, mice were treated with H2 and O2, which were generated by electrolyzing deionized water with a H2 apparatus Hydrogen (67%) and oxygen (33%) were freshly mixed with nitrogen (N2) separated from the air, diluted to a mixture containing hydrogen (42%), oxygen (21%), and nitrogen (37%), which was passed through a rubber tube and inhaled by CS-exposed mice at a flow rate of 3.8 L/min. Each inhalation of H2 lasted 1 hour, twice a day, at intervals of 6 to 8 hours.
Control mice were placed in a closed chamber and ventilated. The animals were then subjected to lung function assessment before dissection for further analysis on day 91. The result showed that:
(1) H2 inhalation attenuates CS-induced lung function decline in mice. Compared with control mice with normal air inhalation, the CS exposed mice presented typical COPD-like lung function decline indicated by increases in;
functional residual capacity (FRC), total lung capacity (TLC), Chord compliance (Cchord), forced vital capacity (FVC), and resistance index (RI), as well as a decrease in the F COPD-like lung function decline indicated by increases in functional residual capacity (FRC), total lung capacity (TLC), Chord compliance (Cchord), forced vital capacity (FVC),
and resistance index (RI), as well as a decrease in the FEV50/ FVC ratio.
CS-caused increases in FRC, TLC, Cchord and decrease in the FEV50/FVC were attenuated by H2 inhalation. CS exposures significantly increased hematocrit value in blood, which was ameliorated by H2 administration. Altogether, these results demonstrate that H2 inhalation improves CS-induced mouse lung function decline and hypoxia-induced packed cell volume elevation.
(2) H2 inhalation attenuates CS-induced emphysema.
Collagen deposition in the small airway and goblet cell hypertrophy, and hyperplasia of airway epithelium. CS-induced lung injury had a typical pathological presentation of COPD, such as damaged alveolar walls and pulmonary bullae, in mouse lungs exposed to CS.
Inhalation of H2 significantly reduced structural damage of the lung and accumulation of leukocytes in both the alveolar walls and spaces. Goblet cells from the airway epithelium of CS-exposed mice, identified by PAS staining, contained large granular stores of PAS-positive substances, which was attenuated in the H2 treatment group. The severe collagen deposition in the small airway (50?499 ?m diameter) in CS-exposed mice were reduced by H2 inhalation.
(Figure 5-1).
EV50/FVC ratio. CS-caused increases in FRC, TLC, Cchord and decrease in the FEV50/FVC were attenuated by H2 inhalation. CS exposures significantly increased hematocrit value in blood, which was ameliorated by H2 administration.
Altogether, these results demonstrate that H2 inhalation ameliorates (makes something bad or unsatisfactory better.) CS-induced mouse lung function decline and hypoxia-induced hematocrit (the ratio of the volume of red blood cells to the total volume of blood.) elevation. (2) H2 inhalation lessens CS-induced emphysema, collagen
deposition in the small airway and goblet cell hypertrophy, and hyperplasia of airway epithelium. CS-induced lung injury had a typical pathological presentation of COPD, such as damaged alveolar walls and pulmonary bullae,
in mouse lungs exposed to CS.
Inhalation of H2 significantly reduced structural damage of the lung and accumulation of leukocytes in both the alveolar walls and spaces. Goblet cells from the airway epithelium of CS-exposed mice, identified by PAS staining, contained large granular stores of PAS-positive substances, which was attenuated in the H2 treatment group. The severe collagen deposition in the small airway (50?499 ?m diameter) in CS-exposed mice were reduced by H2 inhalation (Figure 5-1).
Redox-Related Mechanisms in the Pathophysiology of COVID-19
The cellular redox status can affect the structural composition of various sensitive components found inside or on the surface of the cell. These redox-sensitive components include many proteins/enzymes composed of sulphur-containing amino acids/peptides (SH and S-S) making them sensitive to the redox state of the environment.
Methionine, cysteine (Cys), cystine, homocysteine, glutathione, and hydrogen sulphide are the common sulphur-containing compounds impacting protein regulation and cell signalling. Furthermore, the cofactors such as Fe, Zn, Mg, and Cu found in their oxidized or reduced form, make the cellular enzymes susceptible to the redox change in the environment.
In the same manner, we can discuss the effect of redox value on various redox-sensitive molecules located on the surface of the cell such as enzymes, proteins, phospholipids, and saturated and unsaturated fatty acids, which could become targets for the redox change in the environment/cytoplasm. The modification in the structure of these components can directly affect different functional and structural cellular systems such as cellular transport and bioenergetics.
The cell possesses a redox homeostasis system that regulates many key functions such as protein synthesis, enzyme activity, metabolic pathways, and transport across the membrane. This redox homeostasis can be regulated by different factors such as oxidoreductases (catalase (CAT), superoxide dismutase (SODs), and glutathione peroxidase (GPXs)), metallic ions (Fe, Cu, Mg, etc.), metabolites (adenosine triphosphate/adenosine monophosphate (ATP/AMP), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and tricarboxylic acid cycle (TCA) intermediates), gaseous-signalling molecules (ROS, H2, H2S, CO, NO?, etc.), and internal antioxidants (ascorbate, vitamin E, ?-carotene, urate, and thiols).
Amino acids and their macromolecules, i.e., peptides and proteins, can affect and be affected by the redox state of the cytoplasm and environment. The amino acids, peptides, and proteins containing thiols (SH) form the targets for oxidants such as ROS [49]. The production of ROS and/or the change in the thiols/disulphide ratio led to the perturbation of the intracellular redox homeostasis.
This critical situation leads the cell to sense redox signalling, and thus regulate the cellular redox state [49]. When the levels of the generated ROS are high, the cell can use the redox-sensitive signalling pathways and transcription factors to upregulate genes encoding reductants such as thiols, enzymes, thioredoxin (Trxs), and glutaredoxins (Glrxs) that will reset redox homeostasis [49].
However, when the situation is more severe with very high levels of ROS, for example, during acute injury or inflammation, damage occurs to various macromolecules and cellular structures and functions, which can lead to irreversible injury and cell death. The presence of molecular hydrogen in the last case can mitigate the cytotoxic effects of ROS by reducing only the most aggressive ones, i.e., ?OH and ONOO?, without affecting the physiologically beneficial ROS-dependent signalling molecules, i.e., O2??, H2O2, and ?NO, and thus, maintaining redox homeostasis of the cell [52].
The modification of the structural composition of proteins due to the change of thiol (SH) to the disulphide (S-S) form impairs molecular chaperoning, translation, metabolism, cytoskeletal structure, cell growth, and signal transduction. Additionally, the formation of disulphide bonds affects the conformation of redox-sensitive proteins [58]. It was reported that in an oxidizing medium, the sulphur group in cysteine can form intramolecular disulphide bonds creating a reversible cross-link that can be broken in the presence of a reducing agent [87]. Oxidative stress conditions are characterized by a high generation of ROS and are related to many diseases involving disulphide bond formation [87]. Thiol-disulphide reactions follow an exchangeable and rate-dependent bond rupture mechanism [87].
Inflammasome activation by ROS induced by viruses. Intracellular overgeneration of ROS through NADPH oxidase or mitochondrial ETC is
sensed by a complex of Trx and thioredoxin interacting protein (TXNIP), which dissociates and enables the binding of TXINP with NLRP3. This is followed by activation of NLRP3 and recruitment of apoptosis-associated speck-like protein (ASC) and pro-caspase1/12 proteins, leading to formation of active inflammasome. Active NLRP3 inflammasome cleaves pro-interleukin-1 (IL-1) beta and pro-IL-18 to active IL1 beta and IL-18, which induce cytokine storm subsequently. ETC: Electron transport chain. Modified from Zhou, et al. [2010].
Based on the simplicity of the therapy
The convenience of any clinical treatment is very important, especially for severe patients. The hydrogen-oxygen inhalation system uses a nasal catheter or mask inhalation method , which can be used alone or together with conventional oxygen inhalation and mechanically assisted breathing. Since the inhaled hydrogen-oxygen mixed gas contains 34% oxygen, it is actually equivalent to simultaneous oxygen inhalation. In view of the simplicity of the method of use, the hydrogen-oxygen inhalation therapy can be used in rehabilitation centers or at home for patients in the rehabilitation period.
The hydrogen-oxygen inhalation therapy can be used in hospital or at home.
At COVID-19 treatment centers, many patients appear very excited and grateful as their symptoms improve after receiving hydrogen- oxygen inhalation therapy. On-site medical staff have recorded many videos of moving scenes. Some typical cases are featured as follows.
Case 1
Female, 63 years old. In early February 2020, there was no obvious cause of dry cough, which gradually worsened, accompanied by wheezing and fatigue. February 2, chest CT examination revealed multiple patchy lesions in both lungs. SpO2 was below 85%. COVID-19 nucleic acid test was positive. Diagnosed as COVID-19. High-flow oxygen inhalation and symptomatic treatment were given. After 2 weeks, the patient?s cough improved and the nucleic acid test turned negative. In the case of mask oxygen supply, the patient?s SpO2 could be maintained at more than 90%, but could not be separated from oxygen inhalation. Breathing was still short, complaining of chest tightness. She started receiving hydrogen- oxygen inhalation on February 28, 8 hours a day. After 2 days, the patient?s shortness of breath and chest tightness disappeared. One week later, the patient could get out of bed and move freely without oxygen inhalation; SpO2 remained above 95%; CT review showed that most of the lung lesions were absorbed (Figure 7-6).
1st Chest CT before hydrogen-oxygen inhalation show multiple patchy lesions in both lungs. 2nd: Chest CT after 14 days of hydrogen-oxygen inhalation show that most of the pulmonary lesions were absorbed.
Case 2
Female, 57 years old. On January 29, 2020, the patient developed fever, cough, and dyspnea, and she received antibiotics, oxygen inhalation, and other symptomatic treatments. Her condition progressed, body temperature rose to 40ºC, SpO2 decreased to 70%, consciousness was blurred, and stool and urinary incontinence developed. Chest CT showed ?large white shadows? on both lungs. Given a ventilator to assist breathing. Half a month later, her body temperature dropped to normal range and her cough improved, but she felt persistent chest tightness and chest pain. In the case of high flow oxygen inhalation, SpO2 could reach 95%, but it quickly decreased to below 90% after stopping oxygen inhalation. A CT scan of the chest on February 16 showed a large number of residual lesions. At 10 am on February 22, the patient began to inhale hydrogen-oxygen. After an hour, the patient felt ?especially comfortable?. Three days later, the patient got rid of the oxygen treatment and ventured to the corridor outside her ward freely. Together with several ?hydrogen friends? who also received hydrogen-oxygen inhalation, she invited the medical staff to take a photo and share their happiness (Figure 7-7). On February 27, chest
1st: Chest CT before hydrogen-oxygen inhalation show multiple patchy lesions in both lungs. 2nd : Chest CT after 14 days of hydrogen-oxygen inhalation show that most of the pulmonary lesions were absorbed.
Case 3
Male, 37 years old. On January 27, 2020, he was admitted to the hospital due to fever, coughing, dyspnea, and wheezing for one week. Chest CT showed diffuse shadows in both lungs and COVID-19 RNA was positive in pharyngeal swabs. SpO2 was reduced to a minimum of 80%. Diagnosed as COVID-19 (severe type), acute respiratory failure. Given high-flow oxygen inhalation through the mask and the nasal canal, as well as intravenous infusion of gamma globulin, albumin, and corticosteroids. After 2 weeks, the body temperature gradually returned to normal range, the cough was decreased, and the lung CT showed an improvement of acute exudative lesions, but the patient still had significant shortness of breath after mild activity. Without oxygen inhalation, SpO2 dropped to about 85%, accompanied by chest tightness and chest pain. From March 11, the patient stopped regular oxygen inhalation and changed to inhalation treatment of hydrogen-oxygen mixed gas (67% hydrogen, 33% oxygen) at a flow rate of 6 L/min, inhaling more than 6 hours a day. The patient?s shortness of breath improved after 3 days, and chest pain and tightness disappeared after a week. SpO2 maintained above 97% without oxygen inhalation. Follow-up CT showed absorption of most inflammation in both lungs (Figure 7-9). Multiple consecutive viral RNA tests showed negative results. On March 16, 2020, the patient was discharged from the hospital.
1st : CT before hydrogen-oxygen inhalation show multiple inflammatory lesions in lungs. 2nd : CT images taken 5 days after inhalation of hydrogen-oxygen show significant absorption of inflammation in both lungs
???????
Conclusion and recommendations
Although COVID-19 is a self-limiting disease, it is extremely contagious. With the global pandemic, there will be more and more deaths. Clinical observations in China have shown that the early symptoms of the disease can be lacking or mild, but after a period of time, the condition can worsen dramatically. Once severe, the mortality rate reaches 60%. Hydrogen has a wide range of biological effects. Therefore, in the comprehensive treatment of COVID-19, it is reasonable and feasible to offer the hydrogen-oxygen inhalation therapy.
According to existing research and experience, the clinical application of hydrogen-oxygen treatment must follow the following principles:
· Hydrogen and oxygen mixed gas should be inhaled, not pure hydrogen. Inhaling 33% of O2 is physiologically desirable. Hydrogen can bring oxygen deep into the airways, improving oxygen supply. Inhalation of pure hydrogen will ?squeeze out? oxygen and cause hypoxia;
· High concentration of hydrogen should be inhaled, and it is hoped that hydrogen will fill the entire body in a short time. The currently set hydrogen concentration is 67%;
· The inhaled gas should have a sufficient flow rate. When treating severe patients with airway resistance, the flow rate must not be less than 600 ml/min; The inhalation time should be long enough and not less than 2 hours/day; in severe cases, it should be more than 6 hours/day;
· Nasal catheter or mask can be used for inhalation. Patients should be trained to ensure that normal breathing is consistent with ?inhaled hydrogen?.
In view of the uncertainty of COVID-19, as well as the simplicity and cheapness of this treatment method, hydrogen-oxygen inhalation is recommended for most or all patients, and it is particularly recommended for the following cases:
· For ordinary patients. The purpose of conventional hydrogen-oxygen inhalation is to improve symptoms, especially dyspnea, and to prevent progression to severe illness;
· For critically ill patients. In comprehensive treatment, especially in cases receiving hyperoxia inhalation and mechanical ventilation, hydrogen-oxygen inhalation can improve the efficacy and relieve hyperoxia- or mechanical ventilation-induced lung injury while ensuring sufficient oxygen For patients in recovery. Hydrogen-oxygen inhalation can eliminate residual symptoms and is expected to prevent or reduce pulmonary fibrosis and possible sequelae. Using this treatment at home is recommended.
References
1. Akagi J, Baba H. (2019). Hydrogen gas restores exhausted CD8+ T cells in patients with advanced colorectal cancer to improve prognosis. Oncol Rep. 41(1), pp. 301?311.
2. Akaike T, Nishida M, Fujii S. (2013). Regulation of redox signalling by an electrophilic cyclic nucleotide. J Biochem. 153(2), pp. 131?138.
3. Akira M, Suganuma N. (2014). Acute and subacute chemical-induced lung injuries: HRCT findings. Eur J Radiol. 83(8), pp. 1461?1469.
4. Al-Jamal R, Ludwig MS. (2001). Changes in proteoglycans and lung tissue mechanics during excessive mechanical ventilation in rats. Am J Physiol Lung Cell Mol Physiol. 281, pp. L1078?1087.
5. Altemeier WA, Sinclair SE. (2007). Hyperoxia in the intensive care unit: Why more is not always better. Curr Opin Crit Care. 13(1), pp. 73?78.
6. Altenhöfer S, Radermacher KA, Kleikers PW, et al. (2015). Evolution of NADPH oxidase inhibitors: selectivity and mechanisms for target engagement. Antioxid Redox Signal. 23(5), pp. 406?427.
7. Amatore D, Sgarbanti R, Aquilano K, et al. (2015). Influenza virus replication in lung epithelial cells depends on redox-sensitive pathways activated by NOX4-derived ROS. Cell Microbiol. 17(1), pp. 131?145.
8. Angus D, Yang L, Kong L, et al. (2007). Circulating high-mobility group box 1 (HMGB1) concentrations are elevated in both uncomplicated pneumonia and pneumonia with severe sepsis. Crit Care Med. 35(4), pp. 1061?1067.
9. Aubert RD, Kamphorst AO, Sarkar S, Vezys V. (2011). Antigen-specific CD4 T -cell help rescues exhausted CD8 T cells during chronic viral infection. Proc Natl Acad Sci USA. 108, pp. 21182?21187.
10. Audi SH, Jacobs ER, Zhang X, et al. (2017). Protection by inhaled hydrogen therapy in a rat model of acute lung injury can be tracked in vivo using molecular imaging. Shock. 48(4), pp. 467?476.
11. Bao X, Sinha M, Liu T, et al. (2008). Identification of human metapneumovirus-induced gene networks in airway epithelial cells by microarray analysis. Virology. 374(1), pp. 114?127.
12. Barton LM, Duval EJ, Stroberg E, Ghosh S, Mukhopadhyay S. (2020). COVID-19 autopsies, Oklahoma, USA. Am J Clin Pathol. pii: aqaa062.
13. Beijing Group of National Research Project for SARS. (2003). Dynamic changes in blood cytokine levels as clinical indicators in severe acute respiratory syndrome. Chin Med J (Engl). 116, pp. 1283?1287.
14. Belding ME, Klebanoff SJ, Ray CG. (1970). Peroxidase-mediated virucidal systems. Science.167(3915), pp. 195?196.
15. Bhandari V, Rayman Choo-Wing R, et al. (2006). Hyperoxia causes angiopoietin 2?mediated acute lung injury and necrotic cell death. Nat Med. 12(11), pp. 1286?1293.
16. Bo L, Li C, Chen M, et al. (2018). Application of electrocautery needle knife combined with balloon dilatation versus balloon dilatation in the treatment of tracheal fibrotic scar stenosis. Respiration. 95, pp. 182?187.
17. Brigham KL. (1986) Role of free radicals and lung injury. Chest. 89(6), pp. 859?863.
18. Brydon EW, Morris SJ, Sweet C. (2005). Role of apoptosis and cytokines in influenza virus morbidity. FEMS Microbiol Rev. 29(4), pp. 837?850.
19. Buchholz BM, Kaczorowski DJ, Sugimoto R, et al. (2008). Hydrogen inhalation ameliorates oxidative stress in transplantation induced intestinal graft injury. Am J Transplant. 8(10), pp. 2015?2024.
20. Bulua AC, Simon A, Maddipati R, et al. (2011). Mitochondrial reactive oxygen species promote production of proinflammatory cytokines and are elevated in TNFR1-associated periodic syndrome (TRAPS). J Exp Med. 208(3), pp. 519?533.
21. Bysani GK, Kennedy TP, Ky N, et al. (1990). Role of cytochrome P-450 in reperfusion injury of the rabbit lung. J Clin Invest. 86, pp. 1434?1441
22. Casola A, Garofalo RP, Haeberle H, et al. (2001). Multiple cis regulatory elements control RANTES promoter activity in alveolar epithelial cells infected with respiratory syncytial virus. J Virol. 75(14), pp. 6428?6439.
23. Chalmers S, Khawaja A, Wieruszewski PM, et al. (2019). Diagnosis and treatment of acute pulmonary inflammation in critically ill patients: The role of inflammatory biomarkers. World J Crit Care Med. 8(5), pp. 59?71.
24. Channappanavar R and Perlman S. (2017). Pathogenic human coronavirus infections: Causes and consequences of cytokine storm and immunopathology. Semin Immunopathol. 39(5), pp. 529?539.
25. Channappanavar R and Perlman S. (2020). Evaluation of activation and inflammatory activity of myeloid cells during pathogenic human coronavirus infection. Methods Mol Biol. 2099, pp. 195?204.
26. Channappanavar R, et al. (2016). Dysregulated type I interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in SARS-CoV-infected mice. Cell Host Microbe. 19(2), pp. 181?193.
27. Chapman KE, Sinclair SE, Zhuang D, et al. (2005). Cyclic mechanical strain increases reactive oxygen species production in pulmonary epithelial cells. Am J Physiol Lung Cell Mol Physiol. 289, pp. L834?841.
28. Chen C , Zhang XR , Ju ZY, He WF. (2020). [Advances in the research of mechanism and related immunotherapy on the cytokine storm induced by coronavirus disease 2019]. Zhonghua Shao Shang Za Zhi. 36(6), pp. 471?475. [in Chinese].
29. Chen J, Qi T, Liu L, et al. (2020). Clinical progression of patients with COVID-19 in Shanghai, China. J Infect. pii: S0163-4453(20) 30119-5.
30. Chen JB, Kong XF, Xu KC, et al. (2019).?Real world survey? of hydrogen- controlled cancer: A follow-up report of 82 advanced cancer patients. Med Gas Res. 9(3), pp. 115?121.
31. Chen JB, Qian W, Xu KC, et al. (2020). Hydrogen reverse of immune senescence in NSCLC patients. Med Gas Res. (in press)
32. Chen N, Zhou M, Dong X, et al. (2020). Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study. Lancet. 395(10223), pp. 507?513.
33. Chen X, Wang K, Xing Y, et al. (2014). Coronavirus membrane-associated papain-like proteases induce autophagy through interacting with Beclin1 to negatively regulate antiviral innate immunity. Protein Cell. 5, pp. 912?927.
34. Cho HY, Jedlicka AE, Reddy SP, et al. (2002). Linkage analysis of susceptibility to hyperoxia. Nrf2 is a candidate gene. Am J Respir Cell Mol Biol. 26, pp. 42?51
35. Choi G, Wolthuis EK, Bresser P, et al. (2006). Mechanical ventilation with lower tidal volumes and positive end-expiratory pressure prevents alveolar coagulation in patients without lung injury. Anesthesiology. 105, pp. 689?695.
36. Chu H, Zhou J,Wong BH-Y, et al. (2016). Middle East respiratory syndrome coronavirus efficiently infects human primary Tlymphocytes and activates the extrinsic and intrinsic apoptosis pathways. J Infect Dis. 213(6), pp. 904?914.
37. Circu ML. and Aw TY. (2010). Reactive oxygen species, cellular redox systems, and apoptosis. Free Radic Biol Med. 48, pp. 749?762.
38. Comstock AT, Ganesan S, Chattoraj A,,et al. (2011). Rhinovirus-induced barrier dysfunction in polarized airway epithelial cells is mediated by NADPH oxidase 1. J Virol. 85(13), pp. 6795?6808.
39. COVID-19 Infectious Pneumonia Diagnosis and Treatment Plan (Trial Version 7). China National Health Committee and the State Administration of Traditional Chinese Medicine.2020.
40. Crawford A, Angelosanto JM, Kao C, et al. (2014). Molecular and transcriptional basis of CD4+ T cell dysfunction during chronic infection. Immunity. 40(2), pp. 289?302.
41. Daiber A, Steven S, Weber A, et al. (2017). Targeting vascular (endothelial) dysfunction. Br J Pharmacol. 174(12), pp. 1591?1619.
42. Damiani E, Adrario E, Girardis M, et al. (2014). Arterial hyperoxia and mortality in critically ill patients: A systematic review and meta-analysis. Crit Care. 18, pp. 711.
43. Diao M, Zhang S, Wu L, et al. (2016). Hydrogen gas inhalation attenuates seawater instillation-induced acute lung injury via the Nrf2 pathway in rabbits. Inflammation. 39(6), pp. 2029?2039.
44. Dias-Freitas F, Metelo-Coimbra C, et al. (2016). Molecular mechanism underlying hyperoxia acute lung injury. Respir Med. 119, pp. 23?28
45. Dikalov S. (2011). Cross talk between mitochondria and NADPH oxidases. Free Radic Biol Med. 51(7), pp. 1289?1301.
46. Dole M, Wilson FR, Fife WP. (1975). Hyperbaric hydrogen therapy: a possible treatment for cancer. Science. 190(4210), pp. 152?154.
47. Dolinay T, Kim YS, Howrylak J, et al. (2012). Inflammasome-regulated cytokines are critical mediators of acute lung injury. Am J Respir Crit Care Med. 185, pp. 1225?1234.
48. Dong A, Yu Y, Wang Y, et al. (2018). Protective effects of hydrogen gas against sepsis-induced acute lung injury via regulation of mitochondrial function and dynamics. Int Immunopharmacol. 65, pp. 366?372.
49. Dos Santos CC and Slutsky AS. (2000). Invited review: Mechanisms of ventilator-induced lung injury: a perspective. J Appl Physiol. 89, pp. 1645?1655.
50. Dreyfuss D and Saumon G. (1998). Ventilator-induced lung injury: Lessons from experimental studies. Am J Respir Crit Care Med. 157, pp. 294?323.
51. Exley AR, Cohen J, Buurman W, et al. (1990). Monoclonal antibody to TNF in severe septic shock. Lancet. 335, pp. 1275?1277.
52. Fan E, Brodie D, Slutsky AS. (2018). Acute respiratory distress syndrome: Advances in diagnosis and treatment. JAMA. 319(7), pp. 698?710.
53. Fan E, Needham DM, Stewart TE. (2005). Ventilatory management of acute lung injury and acute respiratory distress syndrome. JAMA. 294, pp. 2889?2896.
54. Favreau DJ, Meessen-Pinard M, Desforges M, Talbot PJ. (2012). Human coronavirus-induced neuronal programmed cell death is cyclophilin D dependent and potentially caspase dispensable. J Virol. 86(1), pp. 81?93.
55. Fink K, Duval A, Martel A, et al. (2008). Dual role of NOX2 in respiratory syncytial virus- and sendai virus-induced activation of NF-kappaB in airway epithelial cells. J Immunol. 180(10), pp. 6911?6922.
56. Fleming MD, Weigelt JA, Brewer V, McIntire D. (1992). Effect of helium and oxygen on airflow in a narrowed airway. Arch Surg. 127, pp. 956? 959.
57. Frank JA, Pittet J-F, Wray C, Matthay MA. (2008). Protection from experimental ventilator-induced acute lung injury by IL-1 receptor blockade. Thorax. 63, pp. 147?153.
58. Fukuda K, Asoh S, Ishikawa M, et al. (2007). Inhalation of hydrogen gas suppresses hepatic injury caused by ischemia/reperfusion through reducing oxidative stress. Biochem Biophys Res Commun. 361(3), pp. 670?674.
59. Fukumoto J, Cox R Jr, Fukumoto I, et al. (2016). Deletion of ASK1 protects against hyperoxia-induced acute lung injury. PLoS One. 11, pp. e0147652.
60. Fung SY, Yuen KS, Ye ZW, et al. (2020). A tug-of-war between severe acute respiratory syndrome coronavirus 2 and host antiviral defence: Lessons from other pathogenic viruses. Emerg Microbes Infect. 9(1), pp. 558?570.
61. Fung TS, Liu DX. (2019). Human coronavirus: host-pathogen interaction.
Annu Rev Microbiol. 73, pp. 529?557.
62. Gao H, Li LY, Zhang M, Zhang Q. (2016). Inactivated Sendai virus induces apoptosis mediated by reactive oxygen species in murine melanoma cells. Biomed Environ Sci. 29(12), pp. 877?884
63. Gao L, Jiang D, Geng J, et al. (2019). Hydrogen inhalation attenuated bleomycin-induced pulmonary fibrosis by inhibiting transforming growth factor-b1 and relevant oxidative stress and epithelial- to-mesenchymal transition. Exp Physiol. 104(12), pp. 1942?1951.
64. Gassen NC, Niemeyer D, Muth D, et al. (2019). SKP2 attenuates autophagy through Beclin1-ubiquitination and its inhibition reduces MERS-Coronavirus infection. Nat Commun. 10, pp. 5770.
65. Ge L, Yang M, Yang NN, et al. (2017). Molecular hydrogen: A preventive and therapeutic medical gas for various diseases. Oncotarget. 8(60), pp. 102653?102673.
66. Geto Z, Molla MD, Challa F, et al. (2020). Mitochondrial dynamic dysfunction as a main triggering factor for inflammation associated chronic non-communicable diseases. J Inflamm Res. 13, pp. 97?107.
67. Ghadiali SN and Gaver DP. (2008). Biomechanics of liquid-epithelium interactions in pulmonary airways. Respir Physiol Neurobiol. 163(1?3), pp. 232?243.
68. Gharib B, Hanna S, Abdallahi OM, et al. (2001). Anti-inflammatory properties of molecular hydrogen: Investigation on parasite-induced liver inflammation. C R Acad Sci III. 324(8), pp. 719?724.
69. Glauser SC, Glauser EM, Rusy BF. (1969). Influence of gas density and viscosity on the work of breathing. Arch Environ Health. 19, pp. 654? 660.
70. Go HS, Seo JE, Kim KC, et al. (2011). Valproic acid inhibits neural progenitor cell death by activation of NF-?B signaling pathway and up-regulation of Bcl-XL. J Biomed Sci. 18(1), pp. 48.
71. Gong X, Zhang L, Jiang R, et al. (2013). Antiinflammatory effects of mangiferin on sepsis-induced lung injury in mice via up-regulation of heme oxygenase-1. J Nutr. 24, pp. 1173.
72. Gong ZJ, Guan JT, Ren XZ, et al. (2016). [Protective effect of hydrogen on the lung of sanitation workers exposed to haze]. Zhonghua Jie He He Hu Xi Za Zhi. 39(12), pp. 916?923. (in Chinese)
73. Grandvaux N, Mariani M, Fink K. (2015). Lung epithelial NOX/DUOX and respiratory virus infections. Clin Sci (Lond). 128(6), pp. 337?347.
74. Griffiths LM, Doudican NA, Shadel GS, Doetsch PW. (2009). Mitochondrial DNA oxidative damage and mutagenesis in Saccharomyces cerevisiae. Methods Mol Biol. 554, pp. 267?286.
75. Gu J, Gong E, Zhang B, et al. (2005). Multiple organ infection and the pathogenesis of SARS. J Exp Med. 202(3), pp. 415?424.
76. Guan P, Lin XM, Yang SC, et al. (2019). Hydrogen gas reduces chronic intermittent hypoxia-induced hypertension by inhibiting sympathetic nerve activity and increasing vasodilator responses via the antioxidation. J Cell Biochem. 120(3), pp. 3998?4008.
77. Guan P, Sun ZM, Luo LF, et al. (2019). Hydrogen gas alleviates chronic intermittent hypoxia-induced renal injury through reducing iron overload. Molecules. 24(6), pp. pii: E1184.
78. Guan P, Sun ZM, Luo LF, et al. (2019). Hydrogen protects against chronic intermittent hypoxia induced renal dysfunction by promoting autophagy and alleviating apoptosis. Life Sci. 225, pp. 46?54.
79. Guan WJ, Chen RC, Zhong NS (2020). Strategies for the prevention and management of coronavirus disease 2019. Eur Respir. (in press).
80. Guan WJ, Wei CH, Zhong NS. (2020). Hydrogen/oxygen mixed gas inhalation improves disease severity and dyspnea in patients with Coronavirus disease 2019 in a recent multicenter, open-label clinical trial. J Thorac Dis. 12(6), pp. 3448?3452.
81. Guo YR, Cao QD, Hong ZS, et al. (2020). The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak ? an update on the status. Mil Med Res. 7(1), pp. 11.
82. Han KY, Kim KT, Joung JG, et al. (2018). SIDR: simultaneous isolation and parallel sequencing of genomic DNA and total RNA from single cells. Genome Res. 28(1), pp. 75?87.
83. Harijith A, Ebenezer DL, Natarajan V .(2014). Reactive oxygen species at the crossroads of inflammasome and inflammation. Front Physiol. 5, pp. 352.
84. He C and Klionsky DJ. (2009). Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet. 43, pp. 67?93.
85. He JH, Tao HY, Yan YM, et al. (2020). Molecular mechanism of evolution and human infection with SARS-CoV-2. Viruses. 12(4), pp. 428; https:// doi.org/10.3390/v12040428. Hennet T, Ziltener HJ, Frei K, Peterhans E. (1992). A kinetic study of immune mediators in the lungs of mice infected with influenza A virus. J Immunol. 149(3), pp. 932?939.
86. Hirano SI, Ichikawa Y, Kurokawa R, et al. (2020). A ?philosophical molecule,? hydrogen may overcome senescence and intractable diseases. Med Gas Res. 10(1), pp. 47?49.
87. Hoegl S, Bachmann M, Scheiermann P, et al. (2011). Protective properties of inhaled IL-22 in a model of ventilator-induced lung injury. Am J Respir Cell Mol Biol. 44, pp. 369?376.
88. Hoegl S, Boost KA, Czerwonka H, et al. (2009). Inhaled IL-10 reduces biotrauma and mortality in a model of ventilator-induced lung injury. Respir Med. 103, pp. 463?470.
89. Hoetzel A, Dolinay T, Vallbracht S, et al. (2008). Carbon monoxide protects against ventilator-induced lung injury via PPAR-gamma and inhibition of Egr-1. Am J Respir Crit Care Med. 177, pp. 1223?1232.
90. Hong Y, Sun LI, Sun R, et al. (2016). Combination therapy of molecular hydrogen and hyperoxia improves survival rate and organ damage in a zymosan-induced generalized inflammation model. Exp Ther Med. 11(6), pp. 2590?2596.
91. Hosakote YM, Jantzi PD, Esham DL, et al. (2011). Viral-mediated inhibition of antioxidant enzymes contributes to the pathogenesis of severe respiratory syncytial virus bronchiolitis. Am J Respir Crit Care Med. 183(11), pp. 1550?1560.
92. Hosakote YM, Liu T, Castro SM, et al. (2009). Respiratory syncytial virus induces oxidative stress by modulating antioxidant enzymes. Am J Respir Cell Mol Biol. 41(3), pp. 348?357.
93. Huang CL, Wang YM, Li XW, et al. (2020). Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 395(10223), pp. 497?506.
94. Huang CS, Kawamura T, Lee S, et al. (2010). Hydrogen inhalation ameliorates ventilator-induced lung injury. Crit Care. 14(6), pp. R234.
95. Huang CS, Kawamura T, Peng X, et al. (2011). Hydrogen inhalation reduced epithelial apoptosis in ventilator-induced lung injury via a mechanism involving nuclear factor-kappa B activation. Biochem Biophys Res Commun. 408(2), pp. 253?258.
96. Huang CS, Kawamura T, Toyoda Y, Nakao A. (2010). Recent advances in hydrogen research as a therapeutic medical gas. Free Rad Res. 44(9), pp. 971?982.
97. Huang P, Wei S, Huang W, et al. (2019). Hydrogen gas inhalation enhances alveolar macrophage phagocytosis in an ovalbumin-induced asthma model. Int Immunopharmacol. 74, 105646. doi: 10.1016/j. intimp.2019.05.031.
98. Hussin AR and Byrareddy SN. (2020).The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. J Autoimmun. 109, pp. 102433.
99. Iida A, Nosaka N, Yumoto T, et al. (2016). The clinical application of hydrogen as a medical treatment. Acta Med Okayama. 70(5), pp. 331?337.
100. Imai Y, Kawano T, Iwamoto S, et al. (1999). Intratracheal anti-tumor necrosis factor-alpha antibody attenuates ventilator-induced lung injury in rabbits. J Appl Physiol. 87, pp. 510?515.
101. Imai Y, Parodo J, Kajikawa O, et al. (2003). Injurious mechanical ventilation and end-organ epithelial cell apoptosis and organ dysfunction in an experimental model of acute respiratory distress syndrome. JAMA. 289(16), pp. 2104?2112.
102. Ishibashi T. (2019). Therapeutic efficacy of molecular hydrogen: A new mechanistic insight. Curr Pharm Des. 25(9), pp. 946?955.
103. Ishihara G, Kawamoto K, Komori N, Ishibashi T. (2019). Molecular hydrogen suppresses superoxide generation in the mitochondrial complex I and reduced mitochondrial membrane potential. Biochem Biophys Res Commun. 522(4), pp. 965?970.
104. Jaber S, Carlucci A, Boussarsar M. (2001). Helium-oxygen in the postextubation period decreases inspiratory effort. Am J Respir Crit Care Med. 164, pp. 633?637.
105. Janssen YMW, Van Houten B, Borm PJA, Mossman BT. (1993). Biology of disease: Cell and tissue responses to oxidative damage. Lab Invest. 69(3), pp. 261?274.
106. Kallet RH and Matthay MA. (2013). Hyperoxic acute lung injury.
Respir Care. 58(1), pp. 123?141.
107. Kamimura N, Ichimiya H, Iuchi K, Ohta S. (2016). Molecular hydrogen stimulates the gene expression of transcriptional coactivator PGC-1a
to enhance fatty acid metabolism. NPJ Aging Mech Dis. 2, pp. 16008.
108. Kamphorst AO, Wieland A, Nasti T, et al. (2017). Rescue of exhausted CD8 T cells by PD-1-targeted therapies is CD28-dependent. Science. 355(6332), pp. 1423?1427.
109. Kannan S, Shaik Syed Ali P, Sheeza A, Hemalatha K. (2020). COVID-19 (novel coronavirus 2019) ? recent trends. Eur Rev Med Pharmacol Sci. 24(4), pp. 2006?2011.
110. Kawamura T, Higashida K, Muraoka I. (2020). Application of molecular hydrogen as a novel antioxidant in sports science. Oxid Med Cell Longev. 2020, pp. 2328768.
111. Kawamura T, Huang CS, Tochigi N, et al. (2010). Inhaled hydrogen gas therapy for prevention of lung transplant-induced ischemia/ reperfusion injury in rats. Transplantation. 90(12), pp. 1344?1351
112. Kawamura T, Wakabayashi N, Shigemura N, et al. (2013). Hydrogen gas reduces hyperoxic lung injury via the Nrf2 pathway in vivo. Am J Physiol Lung Cell Mol Physiol. 304(10), pp. L646?656.
113. Kensler TW, Wakabayashi N, Biswal S. (2007). Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol. 47, pp. 89?116.
114. Khomich OA, Kochetkov SN, Bartosch B, et al. (2018). Redox biology of respiratory viral infections. Viruses. 10(8), pp. 392.
115. Kim SI, Kwak JH, Zachariah M, et al. (2007). TGF-beta-activated kinase 1 and TAK1-binding protein 1 cooperate to mediate TGF-beta1-induced MKK3-p38 MAPK activation and stimulation of type I collagen. Am J Physiol Renal Physiol. 292, pp. F1471?1478.
116. Kindler E, Jónsdóttir HR, Muth D, et al. (2013). Efficient replication of the novel human betacoronavirus EMC on primary human epithelium highlights its zoonotic potential. MBio. 4, pp. e00611?12.
117. Kohama K, Yamashita H, Aoyama-Ishikawa M, et al. (2015). Hydrogen inhalation protects against acute lung injury induced by hemorrhagic shock and resuscitation. Surgery. 158(2), pp. 399?407.
118. Krähling V, Stein DA, Spiegel M, et al. ( 2009). Severe acute respiratory syndrome coronavirus triggers apoptosis via protein kinase R but is resistant to its antiviral activity. J. Virol. 83(5), pp. 2298?3093.
119. Kress JP and Hall JB. (2014). ICU-acquired weakness and recovery from critical illness. N Engl J Med. 371(3), pp. 287?288.
120. Krizbai IA, Bauer H, Bresgen N, et al. (2005). Effect of oxidative stress on the junctional proteins of cultured cerebral endothelial cells. Cell Mol Neurobiol. 25(1), pp. 129?139.
121. Kumari S, Badana AK, Mohan GM, et al. (2018). Reactive oxygen species: A key constituent in cancer survival. Biomark Insights. 13, pp. 1177 271918755391.
122. Kwak MK, Itoh K, Yamamoto M, Kensler TW. (2002). Enhanced expression of the transcription factor Nrf2 by cancer chemopreventive agents: role of antioxidant response element-like sequences in the nrf2 promoter. Mol Cell Biol. 22(9), pp. 2883?2892.
123. Lake MA. (2020). What we know so far: COVID-19 current clinical knowledge and research. Clin Med (Lond). 20(2), pp. 124?127.
124. Law HK, Cheung CY, Ng HY, et al. (2005). Chemokine up-regulation in SARS-coronavirus-infected, monocyte-derived human dendritic cells. Blood. 106(7), pp. 2366?2374.
125. Lazrak A, Iles KE, Liu G, et al. (2009). Influenza virus M2 protein inhibits epithelial sodium channels by increasing reactive oxygen species. FASEB J. 23(11), pp. 3829?3842.
126. LeBaron TW, Kura B, Kalocayova B, et al. (2019). Hydrogen significantly reduces the effects of oxidative stress. Molecules. 24(11), pp. 2076.
127. Lee CH, Chen RF, Liu JW, et al. (2004). Altered p38 mitogen-activated protein kinase expression in different leukocytes with increment of immunosuppressive mediators in patients with severe acute respiratory syndrome. J Immunol. 172, pp. 7841?7847.
128. Lee JH and Paull TT. (2020). Mitochondria at the crossroads of ATM- mediated stress signaling and regulation of reactive oxygen species. Redox Biol. 32, pp. 101511.
129. Levander OA. (1997). Nutrition and newly emerging viral diseases: An overview. J Nutr. 127(5), pp. 948S?950S.
130. Levitt MD. (1969). Production and excretion of hydrogen gas in man.
N Engl J Med. 281(3), pp. 122?127.
131. Levitt MD. (1980). Intestinal gas production--recent advances in flatology. N Engl J Med. 302(26), pp. 1474?1475.
132. Li J and Fan JG. (2020). Characteristics and mechanism of liver injury in 2019 coronavirus disease. J Clin Transl Hepatol. 8(1), pp. 13?17.
133. Li L, Li X, Zhang Z, Liu L, et al. (2020). Protective mechanism and clinical application of hydrogen in myocardial ischemia-reperfusion injury. Pak J Biol Sci. 23(2), pp. 103?112.
134. Li PC, Wang BR, Li CC, et al. (2018). Seawater inhalation induces acute lung injury via ROS generation and the endoplasmic reticulum stress pathway. Int J Mol Med. 41(5), pp. 2505?2516.
135. Li S, et al. (2016) 5-Aminolevulinic acid combined with ferrous iron ameliorate ischemia-reperfusion injury in the mouse fatty liver model. Biochem Biophys Res Commun. 470, pp. 900?906.
136. Li SW, Fujino M, Ichimaru N, et al. (2018). Molecular hydrogen protects against ischemia-reperfusion injury in a mouse fatty liver model via regulating HO-1 and Sirt1 expression. Sci Rep. 8, pp. 14019.
137. Li SW, Wang CY, Jou YJ, et al. (2016). SARS coronavirus papain-like protease induces Egr-1-dependent up-regulation of TGF-b1 via ROS/ p38 MAPK/STAT3 pathway. Sci Rep. 6, pp. 25754.
138. Li W, Yang S, Yu FY, et al. (2018). Hydrogen ameliorates chronic intermittent hypoxia-induced neurocognitive impairment via inhibiting oxidative stress. Brain Res Bull. 143, pp. 225?233.
139. Li Y, Xie K, Chen H, Wang G, Yu Y. (2015). Hydrogen gas inhibits high- mobility group box 1 release in septic mice by upregulation of heme oxygenase 1. J Surg Res. 196(1), pp. 136?148.
140. Li YC, Bai WZ, Hashikawa T. (2020). The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients. J Med Virol. doi: 10.1002/jmv.25728.
141. Liang C1, Liu X, Liu L, He D. (2012). [Effect of hydrogen inhalation on p38 MAPK activation in rats with lipopolysaccharide- induced acute lung injury]. Nan Fang Yi Ke Da Xue Xue Bao. 32(8), pp. 1211?1213. (in Chinese)
142. Lin N, Ji ZQ, Huang CW. (2017). Smad7 alleviates glomerular mesangial cell proliferation via the ROS-NF-?B pathway. Exp Cell Res. 361(2), pp. 210?216.
143. Lin X, Wang R, Zou W, et al. (2016). The influenza virus H5N1 infection can induce ROS production for viral replication and host cell death in A549 cells modulated by human Cu/Zn superoxide dismutase (SOD1) overexpression. Viruses. 8(1), pp. 13.
144. Liu DX, Fung TS, Chong KK-L, et al. (2014). Accessory proteins of SARS- CoV and other coronaviruses. Antiviral Res. 109, pp. 97?109.
145. Liu G, Yu YH, Xie KL. (2018). [Effect of high concentration of hydrogen gas inhalation on postoperative delirium in elderly patients receiving hip fracture surgery]. J Clin Anesthesiology. 34, pp. 5?8. (in Chinese)
146. Liu H, Liang X, Wang D, et al. (2015). Combination therapy with nitric oxide and molecular hydrogen in a murine model of acute lung injury. Shock. 43(5), pp. 504?511.
147. Liu J, Zheng X, Tong Q, et al. (2020). Overlapping and discrete aspects of the pathology and pathogenesis of the emerging human pathogenic coronaviruses SARS-CoV, MERS-CoV, and 2019-nCoV. J Med Virol. 92(5), pp. 491?494.
148. Liu W, Shan LP, Dong XS, et al. (2013). Combined early fluid resuscitation and hydrogen inhalation attenuates lung and intestine injury. World J Gastroenterol. 19(4), pp. 492?502.
149. Liu X, Ma C, Wang X, et al. (2017). Hydrogen coadministration slows the development of COPD-like lung disease in a cigarette smoke- induced rat model. Int J Chron Obstruct Pulmon Dis. 12, pp. 1309?1324.
150. Liu, Liu Q, Wang RS. (2020). Anatomy report of the corpse system of a new type of coronavirus pneumonia. Shanghai J Foren Med. [in Chinese]
151. Lu W, Li D, Hu J, et al. (2018). Hydrogen gas inhalation protects against cigarette smoke-induced COPD development in mice. J Thorac Dis. 10(6), pp. 3232?3243.
152. Madahar P and Beitler JR. (2020). Emerging concepts in ventilation- induced lung injury. Version 1. F1000Res. 9, pp. 222.
153. Martinon F, Pétrilli V, Mayor A, et al. (2006). Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 440(7081), pp. 237?241.
154. Meng X, Xu H, Dang Y, et al. (2019). Hyperoxygenated hydrogen-rich solution suppresses lung injury induced by hemorrhagic shock in rats. J Surg Res. 239, pp. 103?114.
155. Mittal M, Siddiqui MR, Tran K, et al. (2014). Reactive oxygen species in inflammation and tissue injury. Antioxid Redox Signal. 20(7), pp. 1126?1167.
156. Moon DH, Kang DY, Haam SJ, et al. (2019). Hydrogen gas inhalation ameliorates lung injury after hemorrhagic shock and resuscitation. J Thorac Dis. 11(4), pp. 1519?1527.
157. Nakahira K, Haspel JA, Rathinam VA, et al. (2011). Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol. 12, pp. 222?230.
158. Nakamura, K. et al. (2017). Macrophage heme oxygenase-1-SIRT1-p53 axis regulates sterile inflammation in liver ischemia-reperfusion injury. J Hepatol. 67(6), pp. 1232?1242.
159. Nencioni A, Wesselborg S, Brossart P. (2003). Role of peroxisome proliferator-activated receptor gamma and its ligands in the control of immune responses. Crit Rev Immunol. 23(1?2), pp. 1?13.
160. Ng CH, Kong SM, Tiong YL, et al. (2014). Selective anticancer copper(II)- mixed ligand complexes: targeting of ROS and proteasomes. Metallomics. 6(4), pp. 892?906.
161. Nguyen T, Nioi P, Pickett CB.(2009). The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem. 284(20), pp. 13291?13295.
162. Nicholls J, Dong XP, Jiang G, Peiris M. (2003). SARS: Clinical virology and pathogenesis. Respirology. 8 Suppl, pp. S6?8.
163. Nicholls JM, Poon LL, Lee KC, et al. (2003). Lung pathology of fatal severe acute respiratory syndrome. Lancet. 361(9371), pp. 1773?1778.
164. Nogueira JE, de Deus JL, Amorim MR, et al. (2020). Inhaled molecular hydrogen attenuates intense acute exercise-induced hippocampal inflammation in sedentary rats. Neurosci Lett. 715, pp. 134577.
165. Nogueira JE, Passaglia P, Mota CMD, et al. (2018). Molecular hydrogen reduces acute exercise-induced inflammatory and oxidative stress status. Free Radic Biol Med. 129, pp. 186?193.
166. Ohsawa I, Ishikawa M, Takahashi K, et al. (2007). Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med. 13, pp. 688?694.
167. Ohta S. (2014). Molecular hydrogen as a preventive and therapeutic medical gas: Initiation, development and potential of hydrogen medicine. Pharmacol Ther. 144(1), pp. 1?11.
168. Opal SM, Fisher CJ, Dhainaut JF, et al. (1997). Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: A phase III, randomized, double- blind, placebo-controlled, multicenter trial. The Interleukin-1 Receptor Antagonist Sepsis Investigator Group. Crit Care Med. 25, pp. 1115?1124.
169. Pagano A and Brazzazzone-Argiroffo C. (2003). Alveolar cell death in hyperoxia-induced lung injury. Ann NY Acad Sci. 1010, pp. 405?416.
170. Palamara AT, Di Francesco P, Ciriolo MR, et al. (1996). Cocaine increases Sendai virus replication in cultured epithelial cells: critical role of the intracellular redox status. Biochem Biophys Res Commun. 228(2), pp. 579?585.
171. Pendyala S, Natarajan V. (2010). Redox regulation of Nox proteins. Respir Physiol Neurobiol. 174(3), pp. 265?271.
172. Perrone LA, Plowden JK, García-Sastre A, et al. (2008). H5N1 and 1918 pandemic influenza virus infection results in early and excessive infiltration of macrophages and neutrophils in the lungs of mice. PLoS Pathog. 4(8), pp. e1000115.
173. Peterhans E. (1997). Oxidants and antioxidants in viral diseases: Disease mechanisms and metabolic regulation. J Nutr. 127(5), pp. 962S?965S.
174. Picca A, Lezza AMS, Leeuwenburgh C, et al. (2017). Fueling inflamm- aging through mitochondrial dysfunction: Mechanisms and molecular targets. Int J Mol Sci. 18(5), pp. 933.
175. Pilcher JE. (1888). Senn on the diagnosis of gastro-intestinal perforation by the rectal insufflation of hydrogen gas. Ann Surg. 8(3), pp. 190?204.
176. Pratt PC. (1958). Pulmonary capillary proliferation induced by O2 ventilation. Am J Pathol. 34(6), pp. 1033?1050.
177. Qian L, Wu Z, Cen J, Pasca S. (2019). Medical application of hydrogen in hematological diseases. Oxid Med Cell Longev. 2019, pp. 3917393.
178. Qiu X, Li H, Tang H, et al. (2011). Hydrogen inhalation ameliorates lipopolysaccharide-induced acute lung injury in mice. Int Immunopharmacol. 11(12), pp. 2130?2137.
179. Ranieri VM, Suter PM, Tortorella C, et al. (1999). Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: A randomized controlled trial. JAMA. 282(1), pp, 54?61.
180. Rogel M. R. et al. (2011). Vimentin is sufficient and required for wound repair and remodeling in alveolar epithelial cells. FASEB J. 25(1), pp. 3873?3883.
181. Rott R, Klenk H-D, NagaiY,Tashiro M. (1995). Influenza viruses, cell enzymes, and pathogenicity. Am J Resp Critl Care Med. 152(4), pp. S16?S19.
182. Rowlands DJ, Naimul Islam M, Das SR, et al. (2011). Activation of TNFR1 ectodomain shedding by mitochondrial Ca2+ determines the severity of inflammation in mouse lung microvessels. J Clin Invest. 121(5), pp. 1986?1999.
183. Saeidi A, Zandi K, Cheok YY, Saeidi H, et al. (2018). T-cell exhaustion in chronic infections: Reversing the state of exhaustion and reinvigorating optimal protective immune responses. Front Immunol. 9, pp. 2569.
184. Saitoh T, Fujita N, Jang MH, et al. (2008). Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature. 456, pp. 264?268.
186. Sato Y, Kajiyama S, Amano A, et al. (2008). Hydrogen-rich pure water prevents superoxide formation in brain slices of vitamin C-depleted SMP30/GNL knockout mice. Biochem Biophys Res Commun. 375, pp. 346?350.
187. Scharping NE, Menk, AV1 Moreci RS, et al. (2016). The tumor microenvironment represses T cell mitochondrial biogenesis to drive intratumoral T cell metabolic insufficiency and dysfunction. Immunity. 45(2), pp. 374?388.
188. Selemidis S, Seow HJ, Broughton BR, et al. (2013). Nox1 oxidase suppresses influenza a virus-induced lung inflammation and oxidative stress. PLoS One. 8(4), pp. e60792.
189. Shanghai Asclepius Meditec Co., Ltd., Shanghai, China. (2019). Summary of clinical trial of hydrogen and oxygen inhalation for AECOPD 2019.
190. Sies H. (2015). Oxidative stress: A concept in redox biology and medicine. Redox Biol. 4, pp. 180?183.
191. Singhal T. (2020).A Review of coronavirus disease-2019 (COVID-19).
Indian J Pediatr. 87(4), pp. 281?286.
192. Skrinskas GJ, Hyland RH, Hutcheon MA. (1983). Using helium-oxygen mixtures in the manage- ment of acute upper airway obstruction. Can Med Assoc J. 128, pp. 555?558.
193. Slutsky AS and Tremblay LN (1998). Multiple system organ failure: Is mechanical ventilation a contributing factor? Am J Resp Crit Care Med. 157, pp. 1721?1725.
194. Smits SL, et al. (2010). Exacerbated innate host response to SARS-CoV in aged non-human primates. PLoS Pathog. 6(2), pp. e1000756.
195. Strocchi A, Ellis CJ, Furne JK, Levitt MD. (1994). Study of constancy of hydrogen-consuming flora of human colon. Dig Dis Sci. 39(3), pp. 494?497.
196. Takata M, Abe J, Tanaka H, et al. (1997). Intraalveolar expression of tumor necrosis factor-alpha gene during conventional and high- frequency ventilation. Am J Respir Crit Care Med. 156, pp. 272?279.
197. Tang W, Pan PF, Huang XQ, et al. (2020). [A pathological report of three COVID-19 cases by minimally invasive autopsies]. Zhonghua Bing Li Xue Za Zhi. 49(0), pp. E009. (in Chinese)
198. Tao G, Song G, Qin S. (2019). Molecular hydrogen: Current knowledge on mechanism in alleviating free radical damage and diseases. Acta Biochim Biophys Sin (Shanghai ). 51(12), pp. 1189?1197.
199. Tateda K, Deng JC, Moore TA, et al. (2003). Hyperoxia mediates acute lung injury and increased lethality in murine legionella pneumonia: The role of apoptosis. J Immunol. 170(8), pp. 4209?4216.
200. Terasaki Y, Ohsawa I, Terasaki M, et al. (2011). Hydrogen therapy attenuates irradiation-induced lung damage by reducing oxidative stress. Am J Physiol Lung Cell Mol Physiol. 301(4), pp. L415?426.
201. Tian S, Hu W, Niu L, et al. (2020). Pulmonary pathology of early-phase 2019 novel coronavirus (COVID-19) pneumonia in two patients with lung cancer. J Thorac Oncol. pii: S1556-0864(20)30132-5.
202. Tisoncik JR, Korth MJ, Simmons CP, et al. (2012). Into the eye of the cytokine storm. Microbiol Mol Biol Rev. 76(1), pp. 16?32.
203. To EE, Broughton BR, Hendricks KS, et al. (2014). Influenza A virus and TLR7 activation potentiate NOX2 oxidase-dependent ROS production in macrophages. Free Radic Res. 48(8), pp. 940?947.
204. Tolle LB, Standiford TJ. (2013). Danger-associated molecular patterns (DAMPs) in acute lung injury. J Pathol. 229(2), pp. 145?156.
205. Tremblay LN, Slutsky AS. (1998). Ventilator-induced injury: From barotrauma to biotrauma. Proc Assoc Am Physicians. 110, pp. 482?488.
206. Tremblay LN, Slutsky AS. (2006). Ventilator-induced lung injury: From the bench to the bedside. Intensive Care Med. 32, pp. 24?33.
207. Tse GM, To KF, Chan PK, et al. (2004). Pulmonary pathological features in coronavirus associated severe acute respiratory syndrome (SARS). J Clin Pathol. 57, pp. 260?265.
208. Turrens JF. (2003). Mitochondrial formation of reactive oxygen species.
J Physiol. 552, pp. 335?344.
209. Unger BL, Ganesan S, Comstock AT, et al. (2014). Nod-like receptor X-1 is required for rhinovirus-induced barrier dysfunction in airway epithelial cells. J Virol. 88(7), pp. 3705?3718.
210. van der Veen TA, de Groot LES, Melgert BN. (2020). The different faces of the macrophage in asthma. Curr Opin Pulm Med. 26(1), pp. 62?68.
211. Venditti P, Di Meo S. [2020]. The role of reactive oxygen species in the life cycle of the mitochondrion. Int J Mol Sci. 21(6), pp. E2173.
212. Vlahos R, Stambas J, Selemidis S. (2012). Suppressing production of reactive oxygen species (ROS) for influenza A virus therapy. Trends Pharmacol Sci. 33, pp. 3?8.
213. Vyas-Read S, Wang W, Kato S, et al. (2014). Hyperoxia induces alveolar epithelial-to-mesenchymal cell transition. Am J Physiol Lung Cell Mol Physiol. 306(4), pp. L326?340.
214. Wang P, Zhao M, Chen Z, et al. (2020). Hydrogen gas attenuates hypoxic-ischemic brain injury via regulation of the MAPK/HO-1/ PGC-1a pathway in neonatal rats. Oxid Med Cell Longev. 2020, pp. 6978784.
215. Weinberg SE, Sena LA, Chandel NS. (2015). Mitochondria in the regulation of innate and adaptive immunity. Immunity. 42(3), pp. 406?417.
216. Wherry EJ, Ha SJ, Kaech SM, et al. (2007). Molecular signature of CD8+
T cell exhaustion during chronic viral infection. Immunity. 27(4), pp. 670?684.
217. Wilson MR, Choudhury S, Takata M. (2005). Pulmonary inflammation induced by high-stretch ventilation is mediated by tumor necrosis
factor signaling in mice. Am J Physiol Lung Cell Mol Physiol. 288, pp. L599?607.
218. Wong CK, Lam CW, Wu AK, et al. (2004). Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. Clin Exp Immunol. 136(1), pp. 95?103.
219. Woodfin A, Voisin MB, Nourshargh S. (2010). Recent developments and complexities in neutrophil transmigration. Curr Opin Hematol. 17, pp. 9?17.
220. Xie K, Yu Y, Huang Y, et al. (2012). Molecular hydrogen ameliorates lipopolysaccharide-induced acute lung injury in mice through reducing inflammation and apoptosis. Shock. 37(5), pp. 548?555.
221. Xie K, Yu Y, Pei Y, et al. (2010). Protective effects of hydrogen gas on murine polymicrobial sepsis via reducing oxidative stress and HMGB1 release. Shock. 34, pp. 90?97.
222. Xiong Y, Liu Y, Cao L, et al. (2020). Transcriptomic characteristics of bronchoalveolar lavage fluid and peripheral blood mononuclear cells in COVID-19 patients. Emerg Microbes Infect. 9(1), pp. 761?770.
223. Xu KC and Chen JB. (2020). Clinical Hydrogen Oncology. Singapore: World Scientific (in press).
224. Xu Z, Shi L, Wang YJ, et al. (2020). Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. https:// pubmed.ncbi. nlm. nih.gov/32085846.
225. Yang N and Shen HM. (2020). Targeting the endocytic pathway and autophagy process as a novel therapeutic strategy in COVID-19. Int J Biol Sci. 16(10), pp. 1724?1731.
226. Yang Q, Liu X, Yao Z, et al. (2014). Penehyclidine hydrochloride inhibits the release of high-mobility group box 1 in lipopolysaccharide-
activated RAW264.7 cells and cecal ligation and puncture-induced septic mice. J Surg Res. 186, pp. 310.
227. Yao W, Guo A, Han X, et al. (2019). Aerosol inhalation of a hydrogen-rich solution restored septic renal function. Aging (Albany NY ). 11(24), pp. 12097?12113.
228. Ye S, Lowther S, Stambas J. (2015). Inhibition of reactive oxygen species production ameliorates inflammation induced by influenza A viruses via upregulation of SOCS1 and SOCS3. J Virol. 89(5), pp. 2672?2683.
229. Ying Y, Xu H, Yao M, Qin Z. (2017). Protective effect of hydrogen- saturated saline on acute lung injury induced by oleic acid in rats. J Orthop Surg Res. 12(1), pp. 134.
230. Yu Y, Yang YY, Yang M, et al. (2019). Hydrogen gas reduces HMGB1 release in lung tissues of septic mice in an Nrf2/HO-1-dependent pathway. Intern Immunopharmacol. 69, pp. 11?18.
231. Zhang H, Liu L, Yu Y, et al. (2016).[Role of Rho/ROCK signaling pathway in the protective effects of hydrogen against acute lung injury in septic mice]. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 28(5), pp. 40?406. (in Chinese)
232. Zhang HL, Liu YF, Luo XR, et al. (2011). Saturated hydrogen saline protects rats from acute lung injury induced by paraquat. World J Emerg Med. 2(2), pp. 149?153.
233. Zhang J, Zhou H, Liu J, et al. (2019). Protective effects of hydrogen inhalation during the warm ischemia phase against lung ischemia- reperfusion injury in rat donors after cardiac death. Microvasc Res. 125, pp. 103885.
234. Zhang N, Deng CW, Zhang XX, et al. (2018). Inhalation of hydrogen gas attenuates airway inflammation and oxidative stress in allergic asthmatic mice. Asthma Res Pract. 4, pp. 3.
235. Zhang ZY, Fang YJ, Luo YJ, et al. (2019). The role of medical gas in stroke: An updated review. Med Gas Res. 9(4), pp. 221?228.
236. Zhao YS, An JR, Yang S, et al. (2019). Hydrogen and oxygen mixture to improve cardiac dysfunction and myocardial pathological changes induced by intermittent hypoxia in rats. Oxid Med Cell Longev. 2019, pp. 7415212.
237. Zhong NS, Zheng ZG, Sun WZ, et al. (2020). Hydrogen/oxygen therapy is superior to oxygen therapy for the treatment an acute exacerbation of chronic obstructive pulmonary disease: results of a multicenter, randomized, double-blind, parallel-group controlled trial (in press).
238. Zhou R, Tardivel A, Thorens B, et al. (2010). Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat Immunol. 11(2), pp. 136?140.
239. Zhou ZQ, Zhong CH, Su ZQ, et al. (2018). Breathing hydrogen-oxygen mixture decreases inspiratory effort in patients with tracheal stenosis. Clin Invest. doi: 1159/ 000492031.
240. Zhu C, Wang X, Huang Z, et al. (2007). Apoptosis-inducing factor is a major contributor to neuronal loss induced by neonatal cerebral hypoxia-ischemia. Cell Death Differ. 14(4), pp. 775?784.
241. Zhu N, Zhang D, Wang W, et al. (2020). A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 382(8), pp. 727?733.
E,O&E Compiled and edited from various publications by KYKSA