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Commentary: Hydrogen: Lightweight molecule takes on a heavyweight problem

  • John N. Kheir
    Affiliations
    Department of Cardiology, Boston Children's Hospital, Boston, Mass

    Department of Pediatrics, Harvard Medical School, Boston, Mass
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  • James A. DiNardo
    Correspondence
    Address for reprints: James A. DiNardo, MD, Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, 300 Longwood Ave, Boston, MA 02115.
    Affiliations
    Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Boston, Mass

    Department of Anaesthesia, Harvard Medical School, Boston, Mass
    Search for articles by this author
      Figure thumbnail fx1
      Effect of H2 in neutralizing damage induced by reactive oxygen species following ischemia.
      Reperfusion following ischemia produces reactive oxygen species O2-•, H2O2, and •OH. These species react with DNA, lipids, and proteins, resulting in cellular injury and death. H2 reduces •OH to H2O.
      See Article page e269.
      Diatomic hydrogen (H2) is the lightest and most abundant molecule in the universe. Hydrogen's reactivity with oxygen is well recognized as a thermodynamically favorable redox reaction that forms water. H2's small size results in unsurpassed diffusivity (even diffusing through steel), enabling it to reach therapeutic targets effectively even in low-flow states. In vivo, inhaled H2 undergoes solubilized transport to the tissues and undergoes redox reactions with reactive oxygen species (ROS) within the mitochondrion, resulting in a substantial arteriovenous difference in dissolved H2 content (∼10 ng/mL).
      • Ohsawa I.
      • Ishikawa M.
      • Takahashi K.
      • Watanabe M.
      • Nishimaki K.
      • Yamagata K.
      • et al.
      Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals.
      Shown in Figure 1, H2 is an ideal therapy for ischemia and reperfusion, where the underlying pathophysiology is mitochondrial oxygen deprivation leading to the subsequent formation of ROS. Unreduced ROS initiate a complex cascade that leads to oxidation of DNA, lipid membranes, and other structures culminating in apoptosis.
      Figure thumbnail gr1
      Figure 1Reperfusion of ischemic organs results in the production of reactive oxygen species, including the superoxide anion radical (O2-•), hydrogen peroxide (H2O2), and the hydroxyl radical (•OH). These oxidant species, particularly •OH, react with DNA, lipids, and proteins, resulting in cellular injury and death when present in high concentrations. H2 has been shown to reduce •OH to H2O. SOD, Superoxide dismutase; HNE, 4-hydroxynonenal; MDA, malondialdehyde.
      In this issue of the Journal, Kimura and colleagues
      • Kimura A.
      • Suehiro K.
      • Mukai A.
      • Fujimoto Y.
      • Funao T.
      • Yamada T.
      • et al.
      Protective effects of hydrogen gas against spinal cord ischemia-reperfusion injury.
      describe a series of well-controlled experiments demonstrating that H2 attenuates the effects of experimental spinal ischemia in a dose-dependent fashion with improved motor function, reduced histopathologic injury, and reduced cerebrospinal fluid glutamate and hydroxyperoxide concentrations. These findings are consistent with a preponderance of evidence that H2's primary effect is related to reactivity with and chemical reduction of oxygen species. In addition to glutamate, mitigation of this central pathology has been shown to alter various signal transduction pathways and gene expression, including calcium-dependent signaling pathways such as nuclear factor of activated T cells,
      • Iuchi K.
      • Imoto A.
      • Kamimura N.
      • Nishimaki K.
      • Ichimiya H.
      • Yokota T.
      • et al.
      Molecular hydrogen regulates gene expression by modifying the free radical chain reaction-dependent generation of oxidized phospholipid mediators.
      nuclear factor kappa-Β,
      • Sobue S.
      • Yamai K.
      • Ito M.
      • Ohno K.
      • Ito M.
      • Iwamoto T.
      • et al.
      Simultaneous oral and inhalational intake of molecular hydrogen additively suppresses signaling pathways in rodents.
      Nrf2, and others.
      • Ichihara M.
      • Sobue S.
      • Ito M.
      • Ito M.
      • Hirayama M.
      • Ohno K.
      Beneficial biological effects and the underlying mechanisms of molecular hydrogen—comprehensive review of 321 original articles.
      Importantly, H2 has shown clinically beneficial effects in a number of preclinical models, including circulatory arrest,
      • Cole A.R.
      • Perry D.A.
      • Raza A.
      • Nedder A.P.
      • Pollack E.
      • Regan W.L.
      • et al.
      Perioperatively inhaled hydrogen gas diminishes neurologic injury following experimental circulatory arrest in swine.
      cardiac arrest,
      • Hayashida K.
      • Sano M.
      • Kamimura N.
      • Yokota T.
      • Suzuki M.
      • Ohta S.
      • et al.
      Hydrogen inhalation during normoxic resuscitation improves neurological outcome in a rat model of cardiac arrest independently of targeted temperature management.
      ,
      • Chen G.
      • Chen B.
      • Dai C.
      • Wang J.
      • Wang J.
      • Huang Y.
      • et al.
      Hydrogen inhalation is superior to mild hypothermia for improving neurological outcome and survival in a cardiac arrest model of spontaneously hypertensive rat.
      stroke,
      • Ohsawa I.
      • Ishikawa M.
      • Takahashi K.
      • Watanabe M.
      • Nishimaki K.
      • Yamagata K.
      • et al.
      Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals.
      sepsis,
      • Xie K.
      • Yu Y.
      • Huang Y.
      • Zheng L.
      • Li J.
      • Chen H.
      • et al.
      Molecular hydrogen ameliorates lipopolysaccharide-induced acute lung injury in mice through reducing inflammation and apoptosis.
      and transplantation.
      • Kawamura T.
      • Huang C.-S.S.
      • Tochigi N.
      • Lee S.
      • Shigemura N.
      • Billiar T.R.
      • et al.
      Inhaled hydrogen gas therapy for prevention of lung transplant-induced ischemia/reperfusion injury in rats.
      Over the past several years, several groups have described the administration of H2 to patients with cardiac arrest,
      • Tamura T.
      • Hayashida K.
      • Sano M.
      • Suzuki M.
      • Shibusawa T.
      • Yoshizawa J.
      • et al.
      Feasibility and safety of hydrogen gas inhalation for post-cardiac arrest syndrome—first-in-human pilot study.
      ,
      • Tamura T.
      • Hayashida K.
      • Sano M.
      • Onuki S.
      • Suzuki M.
      Efficacy of inhaled HYdrogen on neurological outcome following BRain Ischemia during post-cardiac arrest care (HYBRID II trial): study protocol for a randomized controlled trial.
      stroke,
      • Ono H.
      • Nishijima Y.
      • Ohta S.
      • Sakamoto M.
      • Kinone K.
      • Horikosi T.
      • et al.
      Hydrogen gas inhalation treatment in acute cerebral infarction: a randomized controlled clinical study on safety and neuroprotection.
      myocardial infarction,
      • Katsumata Y.
      • Sano F.
      • Abe T.
      • amura T.
      • Fujisawa T.
      • Shiraishi Y.
      • et al.
      The effects of hydrogen gas inhalation on adverse left ventricular remodeling after percutaneous coronary intervention for ST-elevated myocardial infarction—first pilot study in humans.
      and asthma,
      • Niu Y.
      • Nie Q.
      • Dong L.
      • Zhang J.
      • Liu S.F.
      • Song W.
      • et al.
      Hydrogen attenuates allergic inflammation by reversing energy metabolic pathway switch.
      and several trials are ongoing in the setting of coronavirus disease 2019−related respiratory illnesses. Combining results of these studies and preclinical data,
      • Cole A.R.
      • Raza A.
      • Ahmed H.
      • Polizzotti B.D.
      • Padera R.F.
      • Andrews N.
      • et al.
      Safety of inhaled hydrogen gas in healthy mice.
      H2 appears to have a favorable safety profile in a diverse range of clinical settings. Perhaps most important is the environmental safety of handling hydrogen gas mixtures, since mixtures containing an excess of 4% H2 exceed the lower flammability limit and pose a substantial hazard in a clinical setting. This can be overcome through the use of commercially produced, certified, nonflammable hydrogen mixtures that contain less than 4% H2. Specifically, we have shown that 2.4% H2 mixtures with air, oxygen, and oxygen−carbon dioxide mixtures can be attached to the gas inlets of standard ventilators, anesthesia machines, and membrane oxygenators (for cardiopulmonary bypass sweep gases) even in the surgical setting.
      • Cole A.R.
      • Perry D.A.
      • Raza A.
      • Nedder A.P.
      • Pollack E.
      • Regan W.L.
      • et al.
      Perioperatively inhaled hydrogen gas diminishes neurologic injury following experimental circulatory arrest in swine.
      When so arranged, administered H2 concentration remains constant independent of inspired oxygen fraction or cardiopulmonary bypass or ECMO flow rates, and the environmental hazards are eliminated.
      Work to determine whether H2 will prove efficacious in the clinical setting is underway. Our group has recently embarked on a phase I Investigational New Drug trial examining the clinical safety and feasibility of H2 inhalation in healthy adults (NCT04046211). This is the first step in determining whether H2 becomes an important therapeutic in the treatment of clinical conditions in which ischemia and reperfusion play a central role.

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