No matter how much time and money are spent, the successful development of a medical gas therapy, as a new therapeutic tool, is by no means a certainty. Researchers and clinicians should be dedicating effort into the clinically feasible use of medical gas that fulfills the unmet medical needs at the frontline of healthcare.
Nitric Oxide
Nitric oxide (NO) is a colorless and poisonous gas which is generated by automobile and thermal power plants and causes a serious air pollutant. NO concentration in unpolluted air is approximately 0.01 parts per million (ppm). However, NO is an important signaling molecule in the body of mammals and was named ‘Molecule of the Year’ in 1992 [6]. NO plays an important role in vascular homeostasis by its potent vasoregulatory and immunomodulatory properties. Blood vessel dilation is one of the most well-known effects of NO. NO stimulates soluble guanylate cyclase (sGC) and increases cGMP content in vascular smooth muscle cells, resulting in relaxation of vascular tone and vasodilation. In addition to its vasorelaxant effect, NO has a complex spectrum of actions including the regulation of platelet activity and the preservation of the normal structure of the vessel wall. Thus, the actions of NO on blood vessels may increase tissue blood supply and abate the inflammatory response, leading to protection of the tissues from oxidative insults. Inhaled NO is already in clinical use for the treatment of hypoxic respiratory failure and pulmonary hypertension particularly in neonates and additional uses of NO are being investigated in other settings of lung and cardiac diseases [7]. Although multiple single-center studies demonstrated the ability of inhaled NO to improve the outcome of patients with adult ARDS were marginal [8], some studies advocate inhalation of NO as a method to prevent graft injury due to ischemia/reperfusion injury after human lung and liver transplantation.
Carbon Monoxide
Carbon monoxide (CO) is an invisible, chemically inert, colorless and odorless gas and is commonly viewed as an environmental pollutant associated with toxic effects resulting from its ability to compete with oxygen for binding to hemoglobin. CO avidly binds to hemoglobin and forms carboxyhemoglobin (COHb) with an affinity 240 times higher than that of oxygen, resulting in interference with the oxygen-carrying capacity of the blood and consequent tissue hypoxia. Recent basic research has revealed that endogenous CO is an important physiological regulatory factor and exerts anti-inflammatory, anti-apoptotic and organ/cellular protective effects. CO is endogenously and physiologically generated in mammalian cells via the catabolism of heme in the rate-limiting step by heme oxygenase (HO) systems [9]. Potent therapeutic efficacies of CO have been demonstrated using experimental models for many conditions, including paralytic ileus, hemorrhagic shock [10], hyperoxic lung injury, and endotoxemia, supporting the new paradigm that, at low concentrations, CO functions as a signaling molecule that exerts significant cytoprotection. Similarly, bacteria are associated with at least one-third of COPD exacerbations. Toll-like receptors (TLRs) are needed for recognition and clearance of bacteria. In macrophages, CO has recently been shown to inhibit signaling by TLR2, TLR4, TLR5 and TLR9 (but not TLR3) [11]. Soluble forms of CO, such as CO-releasing molecules, may overcome the problem of toxicity and allow clinical application [2].
Hydrogen Sulfide
Hydrogen sulfide (H2S) is a colorless, toxic and flammable gas. It is a naturally occurring gas found in volcanic gases and some well waters and is also responsible for the foul odor of rotten eggs and flatulence. The toxic effects of H2S in humans include eye irritation, shortness of breath, and chest tightness at concentrations <100 ppm. Exposure to H2S at >1,000 ppm may cause severe adverse effects, ranging from loss of consciousness to fatality. H2S is endogenously synthesized normally in vertebrates from L-cysteine, a product of food-derived methionine, by the cystathionone-β-synthase (CBS) and cyctathione-γ-lyase (CSE) system. The enterobacterial flora is another source of H2S. H2S is believed to help regulate body temperature and metabolic activity at physiological concentrations [12]. Also, H2S exerts physiological effects in the cardiovascular system, possibly through modulation of K+-ATP channel opening or as a cellular messenger molecule involved in vascular flow regulation [13]. Administration of H2S produced a ‘suspended animation-like’ metabolic status with hypothermia and reduced oxygen demand [14], thus protecting from lethal hypoxia. This hypometabolic state, which resembles hibernation, induced by H2S may contribute to tolerance against oxidative stress. The effects of a soluble form of H2S (using sodium sulfide) have been under investigation for clinical study on the patients who underwent coronary artery bypass graft (CABG) to potentially reduce the damage done to the heart during surgery.
Hydrogen
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