Hydrogen: A potential new adjuvant therapy for patients with COVID-19Scientific Research
Hydrogen: A Potential New Adjuvant Therapy for COVID-19 Patients
https://doi.org/10.3389/fphar.2020.543718
Fuxun Yang †, 
Ruiming Yue †, Xiaoxiu Luo , 
Rongan Liu * and Xiaobo Huang
Among other things, hydrogen has antioxidant, anti-inflammatory, hormone-modulating and anti-apoptotic properties. According to a review of studies, the use of hydrogen can reduce the damaging cytokine storm and lung damage caused by SARS-CoV-2 during early COVID-19 (Corona Virus Disease 2019), stimulate filamentous sputum drainage, and ultimately reduce the incidence of severe disease Rate. Molecular hydrogen therapy has the potential to become a neoadjuvant therapy for COVID-19, but its efficacy and safety require extensive clinical trials and further confirmation.
Introduction
Since the coronavirus disease 2019 (COVID-19) was first reported in Wuhan in late December 2019, it has rapidly become the sixth largest public health emergency and a matter of international concern (Lai et al., 2020). As of 11:00 a.m. on July 31, 2020, there were 17.328 million confirmed cases worldwide, 670,287 deaths, and an all-cause mortality rate of 3.8%. Also, there are no specific antiviral drugs or vaccines available to prevent COVID-19. Huang et al. (2020) found higher plasma concentrations of IL-2, IL-7, IL-10 and TNF-α in severely or critically ill patients than in other patients. This is consistent with Wang Fushen’s pathological findings (Liu et al., 2020; Xu Z. et al., 2020). Therefore, Chen et al. It has been suggested that cytokine storm is one of the most important factors in the morbidity of critically ill patients (Chen et al., 2020). There are currently no specific drugs available to treat cytokine storm.
Hydrogen is a colorless, odorless and tasteless gas. Inhalation of 2% hydrogen can selectively eliminate hydroxyl radicals (OH) and peroxynitrite anions (ONOO-), significantly improve cerebral ischemia-reperfusion injury in rats, triggering an upsurge in hydrogen-based molecular biology research . To date, the biological effects of hydrogen have been extensively studied. Based on its biological effects, such as B. anti-oxidative, anti-inflammatory, anti-apoptotic and hormonal regulation, hydrogen has been found to be protective against various diseases. In particular, the small-molecule nature of hydrogen allows it to rapidly reach the alveoli, suggesting its unique benefit in lung disease. Given the current epidemic, and based on clinical experience, safety, operability, and simple clinical advertising, this review discusses the feasibility of hydrogen as a means to control and prevent COVID-19.
Conclusions
In conclusion, we hypothesized that early use of hydrogen could attenuate the damage caused by the cytokine storm associated with COVID-19, reduce lung injury, and facilitate drainage of mucous phlegm, thereby reducing morbidity in critically ill patients. So far, only one other article mentions the use of hydrogen to treat COVID-19 patients (Guan et al., 2020). More large-scale randomized controlled trials are needed in the future to clinically verify the efficacy and safety of this treatment.
References
Atsunori, N., Yoshiya, T., Prachi, S., Malkanthi, E., Najla, G. (2010). Effectiveness of Hydrogen Rich Water on Antioxidant Status of Subjects with Potential Metabolic Syndrome-An Open Label Pilot Study. J. Clin. Biochem. Nutr. 46 (2), 140–149. doi: 10.3164/jcbn.09-100
Botek, M., Krejčí, J., McKune, A. J., Sládečková, B., Naumovski, N. (2019). Hydrogen Rich Water Improved Ventilatory, Perceptual and Lactate Responses to Exercise. Int. J. Sports Med. 40 (14), 879–885. doi: 10.1055/a-0991-0268
Channappanavar, R., Perlman, S. (2017). Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin. Immunopathol. 39, 529–539. doi: 10.1007/s00281-017-0629-x
Chen, X., Liu, Q., Wang, D., Feng, S., Zhao, Y., Shi, Y., et al. (2015). Protective Effects of Hydrogen-Rich Saline on Rats with Smoke Inhalation Injury. Oxid. Med. Cell Longev. 2015, 106836. doi: 10.1155/2015/106836
Chen, N., Zhou, M., Dong, X., Qu, J., Gong, F., Han, Y., et al. (2020). Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 395 (10223), 507–513. doi: 10.1016/S0140-6736(20)30211-7
de Jong, M. D., Simmons, C. P., Thanh, T. T., Hien, V. M., Smith, G. J., Chau, T. N., et al. (2006). Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat. Med. 12 (10), 1203–1207. doi: 10.1038/nm1477
Ferrara, J. L. M., Abhyankar, S., Gilliland, D. G. (1993). Cytokine storm of graft-versus-host disease: A critical effector role for interleukin-1. Transplant. Proc. 25 (1 Pt 2), 1216–1217.
Gong, Z. J., Guan, J. T., Ren, X. Z., Meng, D. Y., Yan, X. X. (2016). Protective effect of hydrogen on the lung of sanitation workers exposed to haze. Chinese Journal of Tuberculosis and Respiratory Diseases. 3912 (12), 916–923. doi: 10.3760/cma.j.issn.1001-0939.2016.12.003
Guan, W. J., Wei, C. H., Chen, A. L., Sun, X. C., Guo, G. Y., Zou, X., et al. (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), 3448–3452. doi: 10.21037/jtd-2020-057
Gwarzo, M. Y., Muhammad, A. K. (2010). Extracellular Superoxide Dismutase Activity and Plasma Malondialdehyde in Human Immunodeficiency Virus Subjects of Kano State as Surrogate Markers of CD4 Status. Int. J. Biomed. Sci. Ijbs 6 (4), 294–300.
Hayashida, K., Sano, M., Kamimura, N., Yokota, T., Suzuki, M., Maekawa, Y., et al. (2012). H2 Gas Improves Functional Outcome After Cardiac Arrest to an Extent Comparable to Therapeutic Hypothermia in a Rat Model. J. Am. Heart Assoc. 1 (5), e003459–e003459. doi: 10.1161/JAHA.112.003459
Hayashida, K., Sano, M., Kamimura, N., Yokota, T., Suzuki, M., Ohta, S., et al. (2014). Hydrogen Inhalation During Normoxic Resuscitation Improves Neurological Outcome in a Rat Model of Cardiac Arrest Independently of Targeted Temperature Management. Circulation 132 (24), 2173–2180. doi: 10.1161/CIRCULATIONAHA.114.011848
Hillman, N. H., Moss, T. J., Kallapur, S. G., Bachurski, C., Pillow, J. J., Polglase, G. R., et al. (2007). Brief, large tidal volume ventilation initiates lung injury and a systemic response in fetal sheep. Am. J. Respir. Crit. Care Med. 176 (6), 575–581. doi: 10.1164/rccm.200701-051OC
Hoetzel, A., Dolinay, T., Vallbracht, S., Zhang, Y., Kim, H. P., Ifedigbo, E., 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 (11), 1223–1232. doi: 10.1164/rccm.200708-1265OC
Homma, K., Yoshida, T., Yamashita, M., Hayashida, K., Hayashi, M., Hori, S. (2014). Inhalation of Hydrogen Gas Is Beneficial for Preventing Contrast-Induced Acute Kidney Injury in Rats. Nephron Exp. Nephrol. 128 (3-4), 116–122. doi: 10.1159/000369068
Huang, K. J., Su, I. J., Theron, M., Wu, Y. C., Lai, S. K., Liu, C. C., et al. (2005). An interferon-gamma-related cytokine storm in SARS patients. J. Med. Virol. 75 (2), 185–194. doi: 10.1002/jmv.20255
Huang, C. S., Kawamura, T., Lee, S., Tochigi, N., Shigemura, N., Buchholz, B. M., et al. (2010a). Hydrogen inhalation ameliorates ventilator-induced lung injury. Crit. Care 14 (6), R234. doi: 10.1186/cc9389
Huang, C. S., Kawamura, T., Toyoda, Y., Nakao, A. (2010b). Recent Advances in Hydrogen Research as a Therapeutic Medical Gas. Free Radic. Res. 44 (9), 971–982. doi: 10.3109/10715762.2010.500328
Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., et al. (2020). Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395 (10223), 497–506. doi: 10.1016/S0140-6736(20)30183-5
Igarashi, T., Ohsawa, I., Kobayashi, M., Umemoto, Y., Arima, T., Suzuki, H., et al. (2019). Effects of Hydrogen in Prevention of Corneal Endothelial Damage During Phacoemulsification: A Prospective Randomized Clinical Trial. Am. J. Ophthalmol. 207, 10–17. doi: 10.1016/j.ajo.2019.04.014
Kalil, A. C., Thomas, P. G. (2019). Influenza virus-related critical illness: pathophysiology and epidemiology. Crit. Care 23 (1), 1–7. doi: 10.1186/s13054-019-2539-x
Lai, C.-C., Shih, T.-P., Ko, W.-C., Tang, H.-J., Hsueh, P.-R. (2020). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): The epidemic and the challenges. Int. J. Antimicrobial. Agents 55 (3), 1–9. doi: 10.1016/j.ijantimicag.2020.105924
Laveda, R., Martinez, J., Munoz, C., Penalva, J. C., Perez-Mateo, M. (2006). Different profile of cytokine synthesis according to the severity of acute pancreatitis. World J. Gastroenterol. 11 (34), 5309–5313. doi: 10.3748/wjg.v11.i34.5309
Liu, Q., Zhou, Y. H., Yang, Z. Q. (2015). The cytokine storm of severe influenza and development of immunomodulatory therapy. Cell. Mol. Immunol. 13 (1), 3–10. doi: 10.1038/cmi.2015.74
Liu, Q., Wang, R. S., Qu, G. Q., Wang, Y. Y., Liu, L. (2020). Gross examination report of a COVID-19 death autopsy. Fa Yi Xue Za Zhi 36 (1), 21–23. doi: 10.12116/j.issn.1004-5619.2020.01.005
Ma, L., Zeng, J., Mo, B., Wang, C., Huang, J., Sun, Y., et al. (2015). High mobility group box 1: a novel mediator of Th2-type response-induced airway inflammation of acute allergic asthma. J. Thorac. Dis. 7 (10), 1732–1741. doi: 10.3978/j.issn.2072-1439.2015.10.18
Ning, Y., Yan, S., Huang, H., Zhang, J., Dong, Y., Xu, W., et al. (2013). Attenuation of Cigarette Smoke-Induced Airway Mucus Production by Hydrogen-Rich Saline in Rats. PLoS One 8 (12), e83429. doi: 10.1371/journal.pone.0083429
Ohsawa, I., Ishikawa, M., Takahashi, K., Watanabe, M., Nishimaki, K., Yamagata, K., et al. (2007). Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat. Med. 13 (6), 688–694. doi: 10.1038/nm1577
Perezvilar, J., Mabolo, R., Mcvaugh, C. T., Bertozzi, C. R., Boucher, R. C. (2006). Mucin Granule Intraluminal Organization in Living Mucous/Goblet Cells ROLES OF PROTEIN POST-TRANSLATIONAL MODIFICATIONS AND SECRETION. J. Biol. Chem. 281 (8), 4844. doi: 10.1074/jbc.M510520200
Russell, C. D., Millar, J. E., Baillie, J. K. (2020). Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet 395 (10223), 473–475. doi: 10.1016/S0140-6736(20)30317-2
Rutherford, A., III., Subesinghe, S., Hyrich, K. L., Galloway, J. (2018). Serious infection across biologic-treated patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis. Ann. Rheumatic Dis. A. J. Clin. Rheumatol. Connect. Tissue Res. 77(6), 905–910. doi: 10.1136/annrheumdis-2017-212825
Selvaraj, V, Dapaah-Afriyie, K, Finn, A. (2020). Short-Term Dexamethasone in Sars-CoV-2 Patients. Rhode Island Med. J. 103 (6), 39–43.
Shi, H. M., Zhou, H. C., Jia, Y. R., Wang, Y., Liu, J. F. (2013). The effect of hydrogen on hemorrhagic shock induced acute lung injury in rats. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 25 (6), 347–350. doi: 10.3760/cma.j.issn.2095-4352.2013.06.008
Shimizu, T., Hirano, H., Shimizu, S., Kishioka, C., Sakakura, Y., Majima, Y. (2012). Differential properties of mucous glycoproteins in rat nasal epithelium. A comparison between allergic inflammation and lipopolysaccharide stimulation. Am. J. Respir. Crit. Care Med. 164 (6), 1077–1082. doi: 10.1164/ajrccm.164.6.2012058
Tamura, T., Hayashida, K., Sano, M., Onuki, S., Suzuki, M. (2017). Efficacy of inhaled HYdrogen on neurological outcome following BRain Ischemia During post-cardiac arrest care (HYBRID II trial): study protocol for a randomized controlled trial. Trials 18 (1), 488. doi: 10.1186/s13063-017-2246-3
Taniguchi, K., Karin, M. (2018). NF-κB, inflammation, immunity and cancer: coming of age. Nat. Rev. Immunol. 185 (5), 309–324. doi: 10.1038/nri.2017.142
Voynow, J. A., Gendler, S. J., Rose, M. C. (2006). Regulation of mucin genes in chronic inflammatory airway diseases. Am. J. Respir. Cell Mol. Biol. 34 (6), 661–665. doi: 10.1165/rcmb.2006-0035SF
Wang, S.-T., Bao, C., He, Y., Tian, X., Yang, Y., Zhang, T., et al. (2020). Hydrogen gas (XEN) inhalation ameliorates airway inflammation in asthma and COPD patients. QJM Monthly J. Assoc. Physicians, hcaa:164. doi: 10.1093/qjmed/hcaa164
Xie, K., Yu, Y., Yi, H., Zheng, L., Li, J., Chen, H., et al. (2012). Molecular Hydrogen Ameliorates Lipopolysaccharide-induced Acute Lung Injury in Mice through Reducing Inflammation and Apoptosis. Shock 37 (5), 548–555. doi: 10.1097/SHK.0b013e31824ddc81
Xu, X., Han, M., Li, T., Sun, W., Wei, H. (2020). Effective treatment of severe COVID-19 patients with tocilizumab. Proc. Natl. Acad. Ences 8 (4), 420–422. doi: 10.1073/pnas.2005615117
Xu, Z., Shi, L., Wang, Y., Zhang, J., Huang, L., Zhang, C., et al. (2020). Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respirat. Med. 8 (4), 420–422. doi: 10.1016/S2213-2600(20)30076-X
Zhang, H., Liu, L., Yu, Y., Sun, Z., Liang, Y., Yu, Y. (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), 401–406. doi: 10.3760/cma.j.issn.2095-4352.2016.05.005
DOI: 10.3389
Published on: 15/10/2020
Hydrogen: A Potential New Adjuvant Therapy for COVID-19 Patients
https://doi.org/10.3389/fphar.2020.543718
Fuxun Yang †,
Among other things, hydrogen has antioxidant, anti-inflammatory, hormone-modulating and anti-apoptotic properties. According to a review of studies, the use of hydrogen can reduce the damaging cytokine storm and lung damage caused by SARS-CoV-2 during early COVID-19 (Corona Virus Disease 2019), stimulate filamentous sputum drainage, and ultimately reduce the incidence of severe disease Rate. Molecular hydrogen therapy has the potential to become a neoadjuvant therapy for COVID-19, but its efficacy and safety require extensive clinical trials and further confirmation.
Introduction
Since the coronavirus disease 2019 (COVID-19) was first reported in Wuhan in late December 2019, it has rapidly become the sixth largest public health emergency and a matter of international concern (Lai et al., 2020). As of 11:00 a.m. on July 31, 2020, there were 17.328 million confirmed cases worldwide, 670,287 deaths, and an all-cause mortality rate of 3.8%. Also, there are no specific antiviral drugs or vaccines available to prevent COVID-19. Huang et al. (2020) found higher plasma concentrations of IL-2, IL-7, IL-10 and TNF-α in severely or critically ill patients than in other patients. This is consistent with Wang Fushen’s pathological findings (Liu et al., 2020; Xu Z. et al., 2020). Therefore, Chen et al. It has been suggested that cytokine storm is one of the most important factors in the morbidity of critically ill patients (Chen et al., 2020). There are currently no specific drugs available to treat cytokine storm.
Hydrogen is a colorless, odorless and tasteless gas. Inhalation of 2% hydrogen can selectively eliminate hydroxyl radicals (OH) and peroxynitrite anions (ONOO-), significantly improve cerebral ischemia-reperfusion injury in rats, triggering an upsurge in hydrogen-based molecular biology research . To date, the biological effects of hydrogen have been extensively studied. Based on its biological effects, such as B. anti-oxidative, anti-inflammatory, anti-apoptotic and hormonal regulation, hydrogen has been found to be protective against various diseases. In particular, the small-molecule nature of hydrogen allows it to rapidly reach the alveoli, suggesting its unique benefit in lung disease. Given the current epidemic, and based on clinical experience, safety, operability, and simple clinical advertising, this review discusses the feasibility of hydrogen as a means to control and prevent COVID-19.
Conclusions
In conclusion, we hypothesized that early use of hydrogen could attenuate the damage caused by the cytokine storm associated with COVID-19, reduce lung injury, and facilitate drainage of mucous phlegm, thereby reducing morbidity in critically ill patients. So far, only one other article mentions the use of hydrogen to treat COVID-19 patients (Guan et al., 2020). More large-scale randomized controlled trials are needed in the future to clinically verify the efficacy and safety of this treatment.
References
Atsunori, N., Yoshiya, T., Prachi, S., Malkanthi, E., Najla, G. (2010). Effectiveness of Hydrogen Rich Water on Antioxidant Status of Subjects with Potential Metabolic Syndrome-An Open Label Pilot Study. J. Clin. Biochem. Nutr. 46 (2), 140–149. doi: 10.3164/jcbn.09-100
Botek, M., Krejčí, J., McKune, A. J., Sládečková, B., Naumovski, N. (2019). Hydrogen Rich Water Improved Ventilatory, Perceptual and Lactate Responses to Exercise. Int. J. Sports Med. 40 (14), 879–885. doi: 10.1055/a-0991-0268
Channappanavar, R., Perlman, S. (2017). Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin. Immunopathol. 39, 529–539. doi: 10.1007/s00281-017-0629-x
Chen, X., Liu, Q., Wang, D., Feng, S., Zhao, Y., Shi, Y., et al. (2015). Protective Effects of Hydrogen-Rich Saline on Rats with Smoke Inhalation Injury. Oxid. Med. Cell Longev. 2015, 106836. doi: 10.1155/2015/106836
Chen, N., Zhou, M., Dong, X., Qu, J., Gong, F., Han, Y., et al. (2020). Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 395 (10223), 507–513. doi: 10.1016/S0140-6736(20)30211-7
de Jong, M. D., Simmons, C. P., Thanh, T. T., Hien, V. M., Smith, G. J., Chau, T. N., et al. (2006). Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat. Med. 12 (10), 1203–1207. doi: 10.1038/nm1477
Ferrara, J. L. M., Abhyankar, S., Gilliland, D. G. (1993). Cytokine storm of graft-versus-host disease: A critical effector role for interleukin-1. Transplant. Proc. 25 (1 Pt 2), 1216–1217.
Gong, Z. J., Guan, J. T., Ren, X. Z., Meng, D. Y., Yan, X. X. (2016). Protective effect of hydrogen on the lung of sanitation workers exposed to haze. Chinese Journal of Tuberculosis and Respiratory Diseases. 3912 (12), 916–923. doi: 10.3760/cma.j.issn.1001-0939.2016.12.003
Guan, W. J., Wei, C. H., Chen, A. L., Sun, X. C., Guo, G. Y., Zou, X., et al. (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), 3448–3452. doi: 10.21037/jtd-2020-057
Gwarzo, M. Y., Muhammad, A. K. (2010). Extracellular Superoxide Dismutase Activity and Plasma Malondialdehyde in Human Immunodeficiency Virus Subjects of Kano State as Surrogate Markers of CD4 Status. Int. J. Biomed. Sci. Ijbs 6 (4), 294–300.
Hayashida, K., Sano, M., Kamimura, N., Yokota, T., Suzuki, M., Maekawa, Y., et al. (2012). H2 Gas Improves Functional Outcome After Cardiac Arrest to an Extent Comparable to Therapeutic Hypothermia in a Rat Model. J. Am. Heart Assoc. 1 (5), e003459–e003459. doi: 10.1161/JAHA.112.003459
Hayashida, K., Sano, M., Kamimura, N., Yokota, T., Suzuki, M., Ohta, S., et al. (2014). Hydrogen Inhalation During Normoxic Resuscitation Improves Neurological Outcome in a Rat Model of Cardiac Arrest Independently of Targeted Temperature Management. Circulation 132 (24), 2173–2180. doi: 10.1161/CIRCULATIONAHA.114.011848
Hillman, N. H., Moss, T. J., Kallapur, S. G., Bachurski, C., Pillow, J. J., Polglase, G. R., et al. (2007). Brief, large tidal volume ventilation initiates lung injury and a systemic response in fetal sheep. Am. J. Respir. Crit. Care Med. 176 (6), 575–581. doi: 10.1164/rccm.200701-051OC
Hoetzel, A., Dolinay, T., Vallbracht, S., Zhang, Y., Kim, H. P., Ifedigbo, E., 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 (11), 1223–1232. doi: 10.1164/rccm.200708-1265OC
Homma, K., Yoshida, T., Yamashita, M., Hayashida, K., Hayashi, M., Hori, S. (2014). Inhalation of Hydrogen Gas Is Beneficial for Preventing Contrast-Induced Acute Kidney Injury in Rats. Nephron Exp. Nephrol. 128 (3-4), 116–122. doi: 10.1159/000369068
Huang, K. J., Su, I. J., Theron, M., Wu, Y. C., Lai, S. K., Liu, C. C., et al. (2005). An interferon-gamma-related cytokine storm in SARS patients. J. Med. Virol. 75 (2), 185–194. doi: 10.1002/jmv.20255
Huang, C. S., Kawamura, T., Lee, S., Tochigi, N., Shigemura, N., Buchholz, B. M., et al. (2010a). Hydrogen inhalation ameliorates ventilator-induced lung injury. Crit. Care 14 (6), R234. doi: 10.1186/cc9389
Huang, C. S., Kawamura, T., Toyoda, Y., Nakao, A. (2010b). Recent Advances in Hydrogen Research as a Therapeutic Medical Gas. Free Radic. Res. 44 (9), 971–982. doi: 10.3109/10715762.2010.500328
Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., et al. (2020). Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395 (10223), 497–506. doi: 10.1016/S0140-6736(20)30183-5
Igarashi, T., Ohsawa, I., Kobayashi, M., Umemoto, Y., Arima, T., Suzuki, H., et al. (2019). Effects of Hydrogen in Prevention of Corneal Endothelial Damage During Phacoemulsification: A Prospective Randomized Clinical Trial. Am. J. Ophthalmol. 207, 10–17. doi: 10.1016/j.ajo.2019.04.014
Kalil, A. C., Thomas, P. G. (2019). Influenza virus-related critical illness: pathophysiology and epidemiology. Crit. Care 23 (1), 1–7. doi: 10.1186/s13054-019-2539-x
Lai, C.-C., Shih, T.-P., Ko, W.-C., Tang, H.-J., Hsueh, P.-R. (2020). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): The epidemic and the challenges. Int. J. Antimicrobial. Agents 55 (3), 1–9. doi: 10.1016/j.ijantimicag.2020.105924
Laveda, R., Martinez, J., Munoz, C., Penalva, J. C., Perez-Mateo, M. (2006). Different profile of cytokine synthesis according to the severity of acute pancreatitis. World J. Gastroenterol. 11 (34), 5309–5313. doi: 10.3748/wjg.v11.i34.5309
Liu, Q., Zhou, Y. H., Yang, Z. Q. (2015). The cytokine storm of severe influenza and development of immunomodulatory therapy. Cell. Mol. Immunol. 13 (1), 3–10. doi: 10.1038/cmi.2015.74
Liu, Q., Wang, R. S., Qu, G. Q., Wang, Y. Y., Liu, L. (2020). Gross examination report of a COVID-19 death autopsy. Fa Yi Xue Za Zhi 36 (1), 21–23. doi: 10.12116/j.issn.1004-5619.2020.01.005
Ma, L., Zeng, J., Mo, B., Wang, C., Huang, J., Sun, Y., et al. (2015). High mobility group box 1: a novel mediator of Th2-type response-induced airway inflammation of acute allergic asthma. J. Thorac. Dis. 7 (10), 1732–1741. doi: 10.3978/j.issn.2072-1439.2015.10.18
Ning, Y., Yan, S., Huang, H., Zhang, J., Dong, Y., Xu, W., et al. (2013). Attenuation of Cigarette Smoke-Induced Airway Mucus Production by Hydrogen-Rich Saline in Rats. PLoS One 8 (12), e83429. doi: 10.1371/journal.pone.0083429
Ohsawa, I., Ishikawa, M., Takahashi, K., Watanabe, M., Nishimaki, K., Yamagata, K., et al. (2007). Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat. Med. 13 (6), 688–694. doi: 10.1038/nm1577
Perezvilar, J., Mabolo, R., Mcvaugh, C. T., Bertozzi, C. R., Boucher, R. C. (2006). Mucin Granule Intraluminal Organization in Living Mucous/Goblet Cells ROLES OF PROTEIN POST-TRANSLATIONAL MODIFICATIONS AND SECRETION. J. Biol. Chem. 281 (8), 4844. doi: 10.1074/jbc.M510520200
Russell, C. D., Millar, J. E., Baillie, J. K. (2020). Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet 395 (10223), 473–475. doi: 10.1016/S0140-6736(20)30317-2
Rutherford, A., III., Subesinghe, S., Hyrich, K. L., Galloway, J. (2018). Serious infection across biologic-treated patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis. Ann. Rheumatic Dis. A. J. Clin. Rheumatol. Connect. Tissue Res. 77(6), 905–910. doi: 10.1136/annrheumdis-2017-212825
Selvaraj, V, Dapaah-Afriyie, K, Finn, A. (2020). Short-Term Dexamethasone in Sars-CoV-2 Patients. Rhode Island Med. J. 103 (6), 39–43.
Shi, H. M., Zhou, H. C., Jia, Y. R., Wang, Y., Liu, J. F. (2013). The effect of hydrogen on hemorrhagic shock induced acute lung injury in rats. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 25 (6), 347–350. doi: 10.3760/cma.j.issn.2095-4352.2013.06.008
Shimizu, T., Hirano, H., Shimizu, S., Kishioka, C., Sakakura, Y., Majima, Y. (2012). Differential properties of mucous glycoproteins in rat nasal epithelium. A comparison between allergic inflammation and lipopolysaccharide stimulation. Am. J. Respir. Crit. Care Med. 164 (6), 1077–1082. doi: 10.1164/ajrccm.164.6.2012058
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