Discussion: Protective Effect of Hydrogen Gas Inhalation on Muscular Damage Using a Mouse Hindlimb Ischemia-Reperfusion Injury Model

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Hydrogen gas powers rockets, fuels the fusion reaction of the sun, and now may provide a therapeutic modality to treat ischemia-reperfusion injury. In 1972, hydrogen gas was shown to reduce melanomas in mice.1 Investigators have studied the effects of hydrogen gas in a plethora of disease models with over 50 clinical trials. Hydrogen gas can be administered to patients by means of inhalation, dissolved in an aqueous solution for ingestion, injection, or topical application. At therapeutic dosages, hydrogen gas has no demonstrated toxicity. Given its hydrophobic structure, neutral charge, and small mass, it has excellent distribution to tissues and penetration in biological membranes (peak plasma levels are reached in 30 minutes when inhaled).
One biological mechanism of hydrogen gas is as a potent antioxidant because of its capacity to scavenge toxic oxygen radicals and to up-regulate synergistic antioxidant molecules. This ability has drawn attention to its medical use for the prevention of ischemia-reperfusion injury.2 Surgical complications resulting from ischemia-reperfusion injury remain a major concern for surgeons. Prolonged ischemia of skeletal muscles caused by traumatic subamputation or amputation, elective free tissue transfer, or prolonged tourniquet use manifests as a reduction of muscle mass and function, degeneration of neuromuscular junctions, microvascular damage, failure of free flap anastomosis, and even potential amputation.3,4 Distinct albeit interconnected facets of ischemia-reperfusion injury include the following: (1) the generation of reactive oxygen species, (2) local inflammation and increase in polymorphonuclear cell infiltration, and (3) nonspecific tissue necrosis. Of these three, the rapid generation of reactive oxygen species—notably, hydroxyl radicals—appears first and is directly responsible for the other downstream effects.4 Despite considerable research in prevention of ischemia-reperfusion injury and reactive oxygen species formation, no robust clinical therapeutic options are yet available. In the present study, Watanabe et al. further explore the potential benefit of inhaled hydrogen gas supplementation in a murine model of hindlimb ischemia-reperfusion. The authors found that hydrogen gas inhalation resulted in significant improvement in the histologic appearance of skeletal muscle following ischemia-reperfusion injury, noting decreased areas of necrosis and of polymorphonuclear cell infiltration. A physiologic test analyzing gait further suggested a protective role of hydrogen gas against ischemia-reperfusion injury from a functional perspective.
This study evokes several practical questions regarding the optimal dose, timing, duration, route of administration of the treatment, and its effects on different ischemia times. These are parameters worthy of investigation before translation of findings in a clinical trial. Although an entirely different compound, another therapeutic gaseous molecule, hydrogen sulfide, has also been studied with regard to preventing ischemia-reperfusion injury in the hindlimbs of small animals (e.g., rodents, rabbits)5–7 and in vascularized composite allotransplants in large animals (e.g., swine).8 The authors also suggest that inhalation administration might provide superior outcomes; we would encourage them to compare such strategy to limb (or flap) perfusion, as also shown by Henderson et al.,6 which we believe would provide higher biodistribution within ischemic tissues and more accurately resemble a clinical scenario (e.g., an amputated limb) as compared to here-reported intraperitoneal administration. Further elucidation of the actions by which hydrogen gas exerts its effects is necessary to refine the treatment of ischemia-reperfusion injury itself and to more clearly understand potential clinical benefits. Areas of future investigation may focus on the effects of hydrogen gas preconditioning on ischemia-reperfusion injury–induced peripheral nerve injury, neuromuscular junction degeneration, or systemic organ damage (e.g., kidneys).
Translation of this work to humans will require further evaluation as well. Ichihara et al. compiled a comprehensive review of clinical trials for patients treated with hydrogen gas for a wide range of abnormalities.
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