Hypothesis and Theory ARTICLE
Hydrogen therapy may be a novel and effective treatment for COPD
- Faculty of Naval Medicine, Department of Diving Medicine, Second Military Medical University, Shanghai, People’s Republic of China
The protective effect of hydrogen (H2) on ROS-induced diseases has been proved by many researches, which demonstrated that through eliminating •OH and •ONOO–, H2 could effectively attenuate lipid and DNA peroxidation, improve cellular antioxidant capacity, and then protect cells against oxidant damage. Most of free radicals in human body are ROS, including O2•–,•OH, H2O2, NO•,•ONOO–, and so on. Under normal circumstances cells are able to maintain an adequate homeostasis between the formation and removal of ROS through particular enzymatic pathways or antioxidants. But under some pathological conditions, the balance is disturbed, leading to oxidative stress and various diseases, such as chronic obstructive pulmonary disease (COPD). Studies have shown that ROS played a pivotal role in the development of COPD and some antioxidants were effective in the protection against the damaging effects of oxidative stress. Therefore, we hypothesize that owing to its peculiarity to eliminate toxic ROS, hydrogen therapy may be a novel and effective treatment for COPD.
Hydrogen (H2), a colorless, tasteless, odorless, non-irritating, and highly flammable diatomic gas, was generally regarded as physiologic inert gas in hyperbaric medicine. In 1975 and 2001, Dole et al. (1975) and Gharib et al. (2001) separately reported that H2 under a high pressure might be a therapeutic gas for cancer and parasite-induced liver inflammation by eliminating toxic ROS. In 2007, Ohsawa et al. (2007) found that 2% H2 inhalation exhibited antioxidant and anti-apoptotic activities by selectively reducing cytotoxic oxygen radicals. The importance of H2 immediately drew widespread concerns and it is proved to be effective for many ROS-related diseases, such as hepatic and cardiac hypoxia–ischemia injury, inflammation injury caused by small intestine transplantation and neonatal hypoxia–ischemia injury (Fukuda et al., 2007; Buchholz et al., 2008; Cai et al., 2008; Hayashida et al., 2008). Besides, other ways to administrate H2, such as drinking H2-saturated water, intraperitoneal and intravenous injection of H2-saturated saline, were also effective to many disorders, such as cerebral hypoxia–ischemia injury, human type II diabetes, nephrotoxicity induced by cisplatin, Parkinson’s disease and atherosclerosis in apolipoprotein (Cai et al., 2009; Chen et al., 2009; Mao et al., 2009; Sun et al., 2009; Zheng et al., 2009; Oharazawa et al., 2010). All these evidences show that molecule H2 is effective to diseases related to oxidative stress, which may include chronic obstructive pulmonary disease (COPD).
Chronic Obstructive Pulmonary Disease
Chronic obstructive pulmonary disease is a complex multifactorial disease mainly composed of chronic bronchitis and pulmonary emphysema, which is characterized by not fully reversible airflow limitation. The major feature of COPD is generally accepted as abnormal response to injury, chronic inflammation, excessive activation of macrophages, neutrophils, T lymphocytes, and fibroblasts in the lung. People even with mild COPD often manifest physiological abnormalities that lead to breathlessness and reduction in exercise tolerance, while moderate and severe COPD may remarkably affect the quality of life and mortality.
There are many treatments for COPD, such as inhalational corticosteroid (ICS) and anticholinergics, salmeterol–fluticasone combination (SFC) or tiotropium, and the prescription of antibiotics. However, until now none of them was proved to be an ideal treatment for COPD. ICS could increase the incidence of pneumonia (Drummond et al., 2008). Anticholinergics treatment showed a higher risk of cardiovascular morbidity and mortality (Singh et al., 2008). In another study, tiotropium was showed unable to reduce the decline of FEV1 (Tashkin et al., 2008). Regarding the fact that COPD morbidity and mortality has been increasing in recent years, it would be greatly valuable to find out an effective therapy to COPD.
Oxidative stress is widely proposed as a pathogenic mechanism for COPD (Van der Vliet, 1999; Pinamonti et al., 1996; Repine et al., 1997). Many researchers found markers of oxidative stress, such as H2O2 and NO, in the epithelial lining fluid, breath, and urine of COPD patients (Dekhuijzen et al., 1996; Maziak et al., 1998; Praticò et al., 1998; Montuschi et al., 2000). Oxidant peroxynitrite, generated by the reaction of NO with superoxide anion, is reported to be highly correlated with COPD (Kanazawa et al., 2003). Hydroxyl radical, produced by superoxide anion and H2O2 respectively through the Haber–Weiss reaction and Fenton reaction, is also a strong toxic oxidant (Halliwell and Gutteridge, 1986, 1992). Ichinose found abundant nitrotyrosine positive staining cells and iNOS positive cells in induced sputum of COPD patients, indicating that oxidative stress caused by reactive nitrogen species may be exaggerated in the airways in COPD patients and overproduction of reactive nitrogen species may contribute to pathogenesis of COPD (Ichinose et al., 2000). Accumulating evidences support that ROS is important in the incidence and exacerbation of COPD. First, oxidative stress, such as H2O2 and isoprostane F2a-III formed by free radical peroxidation of arachidonic acid, may induce reversible airway narrowing by constricting airway smooth muscle (Kawikova et al., 1996). Second, oxidants can promote inflammation by activating NF-kB and other pathways. Finally, oxidative stress can lead to a proteinase–antiproteinase imbalance (Park et al., 2009).
Our hypothesis is that H2 may be a unique, effective, and specific treatment for COPD. Given the fact that H2 can eliminate ROS such as •OH and •ONOO– and ROS is an important factor in the pathogenic process in COPD, we hypothesize that H2 may be potentially effective for COPD by preventing its occurrence, exacerbation, and slowing its process.
Compared to other oxidant scavengers, H2 has its special advantages. First, because of its small molecular weight, H2 can easily penetrate bio-membranes and diffuse into cytosol, mitochondria, and nucleus. Second, as H2 selectively reacts with •OH and •ONOO– other important ROS (e.g., H2O2 and ) involved in cell signaling are not decreased, so the metabolic oxidation–reduction reactions are not disturbed. Third, the tissue compatibility of H2 is stronger than many other oxidant scavengers. Especially, in lung the application of H2 has some unique benefits. People have inhaled H2 for hundreds of years in diving and it is already proved to be very safe for inhalation. Moreover, inhaled H2 can easily reach the lung to play a therapeutic role. In addition, because of the special anatomical structure of lung, H2 can reach lung cells easily and quickly; Furthermore, if H2 inhalation is applied as a treatment, H2 will act on lung directly, leading to a better therapeutic effect. In conclusion, as COPD has shown an increase in mortality in recent years, we hope H2 will successfully control the tread due to its potential protective effect.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Buchholz, B. M., Kaczorowski, D. J., Sugimoto, R., Yang, R., Wang, Y., Billiar, T. R., McCurry, K. R., Bauer, A. J., and Nakao, A. (2008). Hydrogen inhalation ameliorates oxidative stress in transplantation induced intestinal graft injury. Am. J. Transplant. 8, 2015–2024.
Cai, J., Kang, Z., Liu, W. W., Luo, X., Qiang, S., Zhang, J. H., Ohta, S., Sun, X., Xu, W., Tao, H., and Li, R. (2008). Hydrogen therapy reduces apoptosis in neonatal hypoxia-ischemia rat model. Neurosci. Lett. 441, 167–172.
Chen, H., Sun, Y. P., Hu, P. F., Liu, W. W., Xiang, H. G., Li, Y., Yan, R. L., Su, N., Ruan, C. P., Sun, X. J., and Wang, Q. (2009). The effects of hydrogen-rich saline on the contractile and structural changes of intestine induced by ischemia-reperfusion in rats. J. Surg. Res. 27, 1–7.
Dekhuijzen, P. N., Aben, K. K., Dekker, I., Aarts, L. P., Wielders, P. L., van Herwaarden, C. L., and Bast, A. (1996). Increased exhalation of hydrogen peroxide in patients with stable and unstable chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 154, 813–816.
Drummond, M. B., Dasenbrook, E. C., Pitz, M. W., Murphy, D. J., and Fan, E. (2008). Inhaled corticosteroids in patients with stable chronic obstructive pulmonary disease: a systematic reviewandmeta-analysis. JAMA 300, 2407–2416.
Fukuda, K., Asoh, S., Ishikawa, M., Yamamoto, Y., Ohsawa, I., and Ohta, S. (2007). Inhalation of hydrogen gas suppresses hepatic injury caused by ischemia/reperfusion through reducing oxidative stress. Biochem. Biophys. Res. Commun. 361, 670–674.
Gharib, B., Hanna, S., Abdallahi, O. M., Lepidi, H., Gardette, B., and De, R. M. (2001). Anti-inflammatory properties of molecular hydrogen: investigation on parasite-induced liver inflammation. C. R. Acad. Sci. III 324, 719–724.
Hayashida, K., Sano, M., Ohsawa, I., Shinmura, K., Tamaki, K., Kimura, K., Endo, J., Katayama, T., Kawamura, A., Kohsaka, S., Makino, S., Ohta, S., Ogawa, S., and Fukuda, K. (2008). Inhalation of hydrogen gas reduces infarct size in the rat model of myocardial ischemia-reperfusion injury. Biochem. Biophys. Res. Commun. 373, 30–35.
Ichinose, M., Sugiura, H., Yamagata, S., Koarai, A., and Shirato, K. (2000). Increase in reactive nitrogen species production in chronic obstructive pulmonary disease airways. Am. J. Respir. Crit. Care Med. 162, 701–706.
Kanazawa, H., Shiraishi, S., Hirata, K., and Yoshikawa, J. (2003). Imbalance between levels of nitrogen oxides and peroxynitrite inhibitory activity in chronic obstructive pulmonary disease. Thorax 58, 106–109.
Kawikova, I., Barnes, P. J., Takahashi, T., Tadjkarimi, S., Yacoub, M. H., and Belvisi, M. G. (1996). 8-Epi-PGF2 alpha, a novel noncyclooxygenase-derived prostaglandin, constricts airways in vitro. Am. J. Respir. Crit. Care Med. 153, 590–596.
Mao, Y. F., Zheng, X. F., Cai, J. M., You, X. M., Deng, X. M., Zhang, J. H., Jiang, L., and Sun, X. J. (2009). Hydrogen-rich saline reduces lung injury induced by intestinal ischemia/reperfusion in rats. Biochem. Biophys. Res. Commun. 381, 602–605.
Maziak, W., Loukides, S., Culpitt, S., Sullivan, P., Kharitonov, S. A., and Barnes, P. J. (1998). Exhaled nitric oxide in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 157, 998–1002.
Montuschi, P., Collins, J. V., Ciabattoni, G., Lazzeri, N., Corradi, M., Kharitonov, S. A., and Barnes, P. J. (2000). Exhaled 8-isoprostane as an in vivo biomarker of lung oxidative stress in patients with COPD and healthy smokers. Am. J. Respir. Crit. Care Med. 162, 1175–1177.
Oharazawa, H., Igarashi, T., Yokota, T., Fuji, H., Suzuki, H., Machide, M., Takahashi, H., Ohta, S., and Ohsawa, I. (2010). Protection of the retina by rapid diffusion of hydrogen: administration of hydrogen-loaded eye drops in retinal ischemia-reperfusion injury. Invest. Ophthalmol. Vis. Sci. 51, 487–492.
Ohsawa, I., Ishikawa, M., Takahashi, K., Watanabe, M., Nishimaki, K., Yamagata, K., Katsura, K., Katayama, Y., Asoh, S., and Ohta, S. (2007). Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat. Med. 13, 688–694.
Pinamonti, S., Muzzoli, M., Chicca, M. C., Papi, A., Ravenna, F., Fabbri, L. M., and Ciaccia, A. (1996). Xanthine oxidase activity in bronchoalveolar lavage fluid from patients with chronic obstructive pulmonary disease. Free Radic. Biol. Med. 21, 147–155.
Praticò, D., Basili, S., Vieri, M., Cordova, C., Violi, F., and Fitzgerald, G. A. (1998). Chronic obstructive pulmonary disease is associated with an increase in urinary levels of isoprostane F2alpha-III, an index of oxidant stress. Am. J. Respir. Crit. Care Med. 158, 1709–1714.
Singh, S., Loke, Y. K., and Furberg, C. D. (2008). Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis. JAMA 300, 1439–1450.
Sun, Q., Kang, Z. M., Cai, J. M., Liu, W. W., Liu, Y., Zhang, J. H., Denoble, P. J., Tao, H., and Sun, X. (2009). Hydrogen-rich saline protects myocardium against ischemia/reperfusion injury in rats. Exp. Biol. Med. 234, 1212–1219.
Tashkin, D. P., Celli, B., Senn, S., Burkhart, D., Kesten, S., Menjoge, S., and Decramer, M. (2008). A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N. Engl. J. Med. 359, 1543–1554.
Keywords: hydrogen, COPD, oxidative stress, antioxidant
Citation: Liu S-L, Liu K, Sun Q, Liu W-W, Tao H-Y and Sun X-J (2011) Hydrogen therapy may be a novel and effective treatment for COPD. Front. Pharmacol. 2:19. doi:10.3389/fphar.2011.00019
Received: 26 November 2010; Paper pending published: 01 February 2011;
Accepted: 28 March 2011; Published online: 12 April 2011.
Edited by:Ruiwen Zhang, University of Alabama at Birmingham, USA
Reviewed by:Xia Liu, Second Military Medical University, China
M. Pilar Gómez-Serranillos, Universidad Complutense, Spain
Copyright: © 2011 Liu, Liu, Sun, Liu, Tao and Sun. This is an open-access article subject to a non-exclusive license between the authors and Frontiers Media SA, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and other Frontiers conditions are complied with.
*Correspondence: Xue-Jun Sun, Faculty of Naval Medicine, Department of Diving Medicine, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, People’s Republic of China. e-mail: firstname.lastname@example.org