activities via the liberation of controlled amounts of CO in biological systems [2]. Recent studies show that nitrate and nitrite, contained in green vegetables, can be recycled in vivo to form NO, representing an important alternative source of NO to the classical L-arginine-NO-synthase pathway, in particular in hypoxic states [3]. It is noteworthy that the enterobacterial flora is an important source of hydrogen and hydrogen sulphide. Experimental study has demonstrated that when hydrogen is released by intestinal bacteria systemic antibiotics may affect the stable levels of these gases along with suppression of commensal bacteria, which may influence to host’s resistance and innate immunity [4].
Application of Medical Gas for Disease
Medical research must be ultimately conducted for human health benefits. Possible therapeutic opportunities for medical gases are shown in table 1. Although every experimental success might not be transferable to standard clinical practice in the near future, the sophisticated experimental concepts of gas inhalation therapy for a medical condition can be considered to be an important step toward clinical application. The medical gas research is relatively unexplored with a short history. Appropriately designed randomized controlled trials with patient-important outcomes, such as improvement of functions of target organs, decreased intensive care unit and hospital days, and decreased cost of therapy, are sorely needed to establish the role of medical gas therapy in patients with disease, associated with the benefits over preexisting standard therapy. At this moment, INOmax®, NO gas for inhalation therapy, is a United States Food and Drug Administration (FDA)-approved drug for the treatment of hypoxic respiratory failure in term and near-term newborns. The drug is also approved by regulatory authorities and used in the clinical setting in Europe, Australia, Asia and Latin America. A European clinical study revealed that inhalation of 100-125 ppm CO by patients with chronic obstructive pulmonary disease in a stable phase was feasible and led to trends in reduction of sputum eosinophils and improvement of responsiveness to methacholine [5]. In the USA, a single-blind, placebo-controlled, dose-escalating phase 2 study of inhaled CO in patients receiving renal transplants is currently conducted using Covox®, a device for CO inhalation. The primary endpoint of the study is to evaluate the safety and tolerability of increasing CO dose levels when administered as an inhaled gas to kidney transplant patients over the course of 1 h in an acute hospital setting. 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
