Abstract
Mechanisms mediating the protective effects of molecular hydrogen (H2) are not well understood. This study explored the possibility that H2 exerts its anti-inflammatory effect by modulating energy metabolic pathway switch. Activities of glycolytic and mitochondrial oxidative phosphorylation systems were assessed in asthmatic patients and in mouse model of allergic airway inflammation. The effects of hydrogen treatment on airway inflammation and on changes in activities of these two pathways were evaluated. Monocytes from asthmatic patients and lungs from ovalbumin-sensitized and challenged mice had increased lactate production and glycolytic enzyme activities (enhanced glycolysis), accompanied by decreased ATP production and mitochondrial respiratory chain complex I and III activities (suppressed mitochondrial oxidative phosphorylation), indicating an energy metabolic pathway switch. Treatment of ovalbumin-sensitized and challenged mice with hydrogen reversed the energy metabolic pathway switch, and mitigated airway inflammation. Hydrogen abrogated ovalbumin sensitization and challenge-induced upregulation of glycolytic enzymes and hypoxia-inducible factor-1α, and downregulation of mitochondrial respiratory chain complexes and peroxisome proliferator activated receptor-γ coactivator-1α. Hydrogen abrogated ovalbumin sensitization and challenge-induced sirtuins 1, 3, 5 and 6 downregulation. Our data demonstrates that allergic airway inflammation is associated with an energy metabolic pathway switch from oxidative phosphorylation to aerobic glycolysis. Hydrogen inhibits airway inflammation by reversing this switch. Hydrogen regulates energy metabolic reprogramming by acting at multiple levels in the energy metabolism regulation pathways.
Highlights
In the past decade, the therapeutic potential of molecular hydrogen (H2) is increasingly recognized[1,2]
Consistent with the increased lactate and decreased ATP production, asthmatic Peripheral blood mononuclear cells (PBMCs) had significantly increased HK and PFK activities (Fig. 1C,D), two key enzymes that catalyze the glycolysis reaction, significantly decreased mitochondrial oxidative phosphorylation (OXPHOS) complex I and III activities (Fig. 1E,F), which catalyze the oxidation-reduction in the mitochondrial electron transport chain, and a decreased citrate synthase (CS) activity (Fig. 1G), the pace-making enzyme in the first step of the Krebs cycle
The enhanced glycolytic activity and repressed OXPHOS activity in association with an increased lactate and decreased ATP production in asthmatic PBMCs suggest that asthma is associated with an energy metabolic pathway switch from OXPHOS to aerobic glycolysis
Summary
The therapeutic potential of molecular hydrogen (H2) is increasingly recognized[1,2]. Activated immune inflammatory cells undergo much the same metabolic pathway switch[23,24,25], which rapidly provides. ATP and metabolic intermediates for the biosynthesis of immune and inflammatory proteins to lunch immune response This metabolic reprogramming has been linked to multiple processes of immune activation[23,24,25,27]. P value and contributes significantly to many pathological processes in which inflammation plays a role Modulation of this energy metabolic reprogramming could be a novel mechanism by which H2, and many other therapeutic agents, exert their anti-inflammatory and protective activities. Neither the effect of H2 on energy metabolic reprogramming nor the mechanisms mediating the H2’s effects have been studied It remains unclear whether allergic inflammation is associated with an energy metabolic pathway switch
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