Biological Responses to Hydrogen Molecule and its Preventive Effects on Inflammatory Diseases

Because multicellular organisms do not have hydrogenase, H₂ has been considered to be biologically inactive in these species, and enterobacteria to be largely responsible for the oxidation of H₂ taken into the body. However, we showed previously that inhalation of H₂ markedly suppresses brain injury induced by focal ischemia-reperfusion by buffering oxidative stress. Although the reaction constant of H₂ with hydroxyl radical in aqueous solution is two to three orders of magnitude lower than that of conventional antioxidants, we showed that hydroxyl radical generated by the Fenton reaction reacts with H₂ at room temperature without a catalyst. Suppression of hydroxyl radical by H₂ has been applied in ophthalmic surgery. However, many of the anti- inflammatory and other therapeutic effects of H₂ cannot be completely explained by its ability to scavenge reactive oxygen species. H₂ administration is protective in several disease models, and preculture in the presence of H₂ suppresses oxidative stress-induced cell death. Specifically, H₂ administration induces mitochondrial oxidative stress and activates Nrf2; this phenomenon, in which mild mitochondrial stress leaves the cell less susceptible to subsequent perturbations, is called mitohormesis. Based on these findings, we conclude that crosstalk between antioxidative stress pathways and the anti-inflammatory response is the most important molecular mechanism involved in the protective function of H₂, and that regulation of the immune system underlies H₂ efficacy. For further medical applications of H₂, it will be necessary to identify the biomolecule on which H₂ first acts.