Recent Advances in Studies of Molecular Hydrogen against Sepsis

Abstract

Sepsis is a syndrome comprised of a series of life-threatening organ dysfunctions caused by a maladjusted body response to infection with no effective treatment. Molecular hydrogen is a new type of antioxidant with strong free radical scavenging ability, which has been demonstrated to be effective for treating various diseases, such as infection, trauma, poisoning, organ ischemia-reperfusion, metabolic diseases, and tumors. Molecular hydrogen exerts multiple biological effects involving anti-inflammation, anti-oxidation, anti-apoptosis, anti-shock, and autophagy regulation, which may attenuate the organ and barrier damage caused by sepsis. However, the underlying molecular mechanisms remain elusive, but are likely related to the signaling pathways involved. This review focuses on the research progress and potential mechanisms of molecular hydrogen against sepsis to provide a theoretical basis for clinical treatment.

Keywords: apoptosis; autophagy; molecular hydrogen; oxidative stress; sepsis; shock.

Figure 1

Molecular hydrogen exerts biological effects. Molecular hydrogen can be ingested in a variety of ways and exerts biological effects, including anti-oxidation, anti-inflammation, anti-apoptosis, anti-shock, and autophagy regulation through scavenging free radicals directly and regulating signal transduction and gene expression indirectly.

Figure 2

The role and mechanisms of Rho GTPase in regulating physiological barriers. Cdc42 and Rac1 in the Rho GTPase family stabilize physiological barriers after activation, while RhoA has dual effects on the barrier. Moderate RhoA activation selectively activates mDia1 signaling to protect the barrier, while excessive activation leads to ROCK-mediated barrier disruption. Cdc42: cell division control protein 42 homolog; Rac1: Ras-related C3 botulinum toxin substrate 1; RhoA: Ras homolog gene family member A; mDia1: mammalian diaphanous-related formin 1; ROCK: Rho-associated coiled-coil protein kinase.

Figure 3

Effects of molecular hydrogen on oxidative stress. Molecular hydrogen antagonizes oxidative stress through multiple pathways, including neutralizing ·OH and ·ONOO-, reducing ·NO production, upregulating antioxidant gene expression (SOD, HO-1, CAT, and MOD), suppressing NADPH oxidase activity, and reducing 8-iso-PGF2α and MDA. ·OH: hydroxyl radicals; ·ONOO-: peroxynitrite anions; SOD: superoxide dismutase; CAT: catalase, MOD: myeloperoxidase; MDA: malondialdehyde; iNOS: inducible nitric oxide synthase; eNOS: endothelial nitric oxide synthase; NADPH oxidase: nicotinamide adenine dinucleotide phosphate oxidase.

Figure 4

Mechanisms of molecular hydrogen against oxidative stress in sepsis. (a) Molecular hydrogen eliminates LPS-induced ROS by direct neutralization, promoting HO-1 expression mediated by Nrf2, and inhibiting LPS-induced ET-1 activation. (b) Molecular hydrogen reduces MDA by inhibiting activation of MAPK and NF-κB signaling induced by LPS. (c) Molecular hydrogen increases antioxidant enzyme activities, such as CAT and SOD. (d) Molecular hydrogen suppresses NADPH oxidase activity. EMT: epithelial-mesenchymal transition; PF: pulmonary fibrosis; BPD: bronchopulmonary dysplasia; Nrf2: nuclear factor erythroid 2-related factor 2; TLR4: toll-like receptor 4; MyD88: myeloid differentiation primary response 88; MDA: malondialdehyde; ROS: reactive oxygen species; HO-1: heme oxygenase 1; CAT: catalase; SOD: superoxide dismutase

Figure 5

Anti-inflammation mechanisms of molecular hydrogen during sepsis. (a) Molecular hydrogen suppresses the NF-κB pathway to reduce pro-inflammatory cytokines by inhibiting IκB-a phosphorylation or suppressing ERK activation mediated by upstream and ASK1. (b) Molecular hydrogen reduces neutrophil aggregation by inhibiting activation of ROS-ASK1-MAPK. (c) Molecular hydrogen attenuates the inflammatory response by activating the Nrf2-mediated HO-1 signaling pathway. ASK1: apoptotic signal-regulated kinase 1; ROS: reactive oxygen species; ERK extracellular regulated kinase; MAPK: mitogen activated protein kinase.

Figure 6

Anti-apoptosis mechanisms of molecular hydrogen in sepsis. Molecular hydrogen suppresses caspases through several pathways: (a) inhibiting ASK1-MAPKs(p38/JNK/ERK)-Bcl-2 activation by neutralizing ROS or suppressing NF-κB; (b) inhibiting p53 activation induced by ROS; (c) activating the PI3K-AKt-GSK3β signaling pathway. PI3K: phosphatidylinositide 3-kinase; AKt: protein kinase B; GSK3β: glycogen synthase kinase 3 beta; ROS: reactive oxygen species.

Figure 7

Anti-shock mechanisms of molecular hydrogen during sepsis. (A) Molecular hydrogen inhibits production of the vasodilator nitric oxide and promotes its consumption. (B) Molecular hydrogen increases ATP production mediated by OXPHOS activation in cardiomyocytes. (C) Molecular hydrogen alleviates vascular endothelial barrier damage mediated by the RhoA/ROCK/mDia signaling pathway and adhesion molecules. AP1: activator protein 1; ELK1: ETS domain-containing protein; OXPHOS: oxidative phosphorylation; Cplx: mitochondrial redox carrier (complex); GLUT: Glucose transporters; ghrelin: growth hormone releasing peptide; FGF21: fibroblast growth factor 21.

Figure 8

Autophagy regulatory mechanisms of molecular hydrogen. (A) Molecular hydrogen has a dual effect on the regulation of autophagy during sepsis. On the one hand, molecular hydrogen suppresses excessive autophagy by inhibiting NF-κB and p38 MAPK, enhancing HO-1, and reducing mTOR suppression induced by reactive oxygen species. On the other hand, molecular hydrogen may enhance autophagy through an unknown mechanism. (B) In studies of ischemia-anoxia reperfusion injury, molecular hydrogen enhances autophagy by inhibiting activation of ERK, mTOR, and Stat3, or by restraining Klotho gene expression. However, molecular hydrogen inhibits AMPK activation by increasing ATP production, which subsequently reduces mTOR suppression and inhibits autophagy. (C) Molecular hydrogen promotes autophagy in orthotopic liver transplantation by activating p53 in the nucleus and increasing target gene expression involving DRAM and ULK. In contrast, molecular hydrogen suppresses autophagy by activating p53 in the cytoplasm. (D) In pathological neuralgia, molecular hydrogen activates HIF-1α and subsequently increases BNIP3 expression or inhibits mTOR, both of which promote autophagy. HI: hypoxia-ischemia; OLT: orthotopic liver transplantation; HIF-1α: hypoxia inducing factor-1; BNIP3: Bcl-2 19 kilodalton interacting protein 3; mTOR: mammalian target of rapamycin; Stat3: signal transducer and activator of transcription 3; AMPK: AMP-activated protein kinase; DRAM: damage regulated autophagy modulator; ULK: Unc-51 like autophagy activating kinase.