Hydrogen (H2) is the lightest and most abundant of chemical elements, constituting nearly 90% of the universe’s elemental mass. In contrast, earth’s atmosphere contains less that 1 ppm of hydrogen. H2 is known to be highly flammable and to violently react with oxidizing elements as typified by the 1937 Hindenberg Zeppelin disaster. Therefore, the use of H2 as a therapeutic agent is not intuitively obvious. However, recent evidence indicates that inhaled H2 gas has antioxidant and anti-apoptotic properties that can protect organs from ischemia-reperfusion-induced injury by selectively scavenging detrimental ROS. The mechanism of action of inhaled H2 gas in these models involves its ability to prevent oxidative damage, as indicated by decreased nucleic acid oxidation and lipid peroxidation [15, 16]. H2-rich liquid such as H2 water represents a novel and easily translatable method of delivery of molecular H2. H2 water may be of potential therapeutic value in the treatment of oxidative stress-induced pathologies as well as inhaling H2 gas [17, 18]. A clinical trial in type 2 diabetic patients given supplemental H2 water led to improved lipid and glucose metabolism compared to controls [19].
Xenon
Xenon is a colorless, odorless noble gas considered chemically inert and unable to form compounds with other molecules. Xenon is a trace gas in Earth’s atmosphere, occurring at <0.087 ± 0.001 ppm and is also found in gases emitted from some mineral springs. Since Cullen and Gross [20] first used xenon on human patients in 1951, xenon has been successfully used in a number of surgical operations as an anesthetic agent. Xenon readily crosses the blood-brain barrier and has low blood/gas solubility, which is advantageous for rapid inflow and washout, associated with good cardiovascular stability and satisfactory sedation [21]. In addition to its anesthetic properties, xenon has protective effects against cerebral ischemia [22]. Decreased blood flow to the brain leads to neuronal death through necrotic and apoptotic mechanisms, which are largely dependent on the activation of the N-methyl-D-aspartate (NMDA) receptor. Since xenon effectively inhibits the NMDA receptor, the neuroprotective effects of xenon may be at least partially due to this inhibition [22-25]. There is evidence suggesting that brief exposure to xenon prevents myocardial ischemia/reperfusion injury.
Helium
Helium is an odorless, tasteless, nonexplosive, noncombustible, nontoxic and physiologically inert gas and has been used safely in the treatment of respiratory disease since 1979 [26, 27]. It diffuses very rapidly to the target organs because of its low atomic weight. It is also nonreactive with body tissues and relatively insoluble in body fluid. The physical properties of helium such as its low density, laminar flow and low driving pressure decrease airway resistance making it an attractive treatment for respiratory diseases that involve a decrease in airway diameter and consequently increased airway resistance, such as bronchial asthma, chronic obstructive pulmonary disease and bronchiolitis. Patients with these conditions may suffer a range of symptoms including breathlessness, hypoxemia and eventually a weakening of the respiratory muscles, which can lead to respiratory failure requiring intubation and mechanical ventilation. Helium can reduce all these effects, making it easier for the patient to breathe by lowered airway resistance, thereby requiring less mechanical energy to ventilate the lungs. Helium is reported to increase in the coronary collateral circulation and enhance the vasodilator effect of inhaled nitric oxide on pulmonary vessels. The physical properties of helium may result in more efficient uptake oxygen and a facilitation of nitrogen egress from affected mitochondria in transient cerebral ischemia, both of which may explain its beneficial effects.
Ozone
Ozone is a triatomic molecule consisting of three oxygen atoms. Ozone is a pale blue gas with a sharp, cold, irritating odor and is produced naturally by electrical discharges following thunderstorms or ultraviolet (UV) rays emitted from the sun. Ozone is present in low concentrations throughout the Earth’s atmosphere; however, an ozone layer exists between 10 and 50 km above from the surface of the earth and plays a very important role filtering UV rays which is critical for the maintenance of biological balance in the biosphere. Ozone gas has a high oxidation potential and is widely used in treatment of water in aquariums and fish ponds to minimize bacterial growth, control parasites, and eliminate transmission of some diseases. Ozone inhalation (0.1-1 ppm) can be toxic to the pulmonary system and cause upper respiratory irritation, rhinitis, headache, and occasionally nausea and vomiting. However, ozone has been used as a therapeutic agent for the treatment of different diseases by creating resistance against oxidative stress via inducing an antioxidative system. Ozone, administered by rectal insufflation, prior to ischemia/reperfusion injury, prevents the damage induced by ROS and attenuates renal and hepatic ischemia/reperfusion injury [28]. Medical applications of blood ozonation via extracorporeal blood oxygenation and ozonation was found to be safe and effective in treating peripheral artery disease in clinical trials [29, 30].
Conclusions
As highlighted above, the ability of medical gases to ameliorate oxidative stress plays an important role at the chemical, cellular and physiological levels. Although some medical gases may cause serious adverse effects, there are still many possible applications of these gases as therapeutic tools for various diseases if the concentrations are tightly controlled. The future of medical gas therapy must focus on the establishment of safe and well-defined administration parameters and on randomized controlled trials to determine the precise indications and guidelines for the use of medical gases in the treatment of various pathologies.
References
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2 Motterlini R, Mann BE, Foresti R: Therapeutic applications of carbon monoxide-releasing molecules. Expert Opin Investig Drugs 2005;14:1305-1318.
3 Lundberg JO, Weitzberg E, Gladwin MT: The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics. Nat Rev Drug Discov 2008;7:156-167.
4 Kajiya M, Sato K, Silva MJ, et al: Hydrogen from intestinal bacteria is protective for concanavalin A-induced hepatitis. Biochem Biophys Res Commun 2009;386:316-321.
5 Bathoorn E, Slebos DJ, Postma DS, et al: Anti-inflammatory effects of inhaled carbon monoxide in patients with COPD: a pilot study. Eur Respir J 2007;30:1131-1137.
