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Hydrogen Gas Therapy Attenuates Inflammatory Pathway Signaling in Septic Mice

Published:February 24, 2021DOI:https://doi.org/10.1016/j.jss.2021.01.022

      Highlights

      • Continuous H2 gas inhalation by septic mice decreased pro-inflammatory cytokines and improved survival.
      • H2 therapy maintained blood glucose level and increased expression of pathways controlling carbohydrate/organic acid metabolism.
      • RNA-seq revealed suppression of potential upstream regulators of inflammatory pathways.

      Abstract

      Background

      Molecular hydrogen (H2) has been used in clinical cases. However, there are few studies of H2 therapy to treat sepsis, and anti-inflammatory mechanisms of H2 are mostly unknown. We aimed to confirm effects of H2 therapy on sepsis and reveal its therapeutic mechanism via RNA sequencing in multiple organs in septic mice.

      Methods

      Nine-week-old C57BL/6 male mice underwent cecal ligation and puncture (CLP) or sham procedure. Subsequently, the CLP model received immediate ± continuous inhalation of 7% H2. Mice were observed for a week to assess survival rates. Serum inflammatory cytokines were evaluated at 24 h after CLP procedure. Liver, intestine, and lungs in CLP mice receiving 24-h ± H2 therapy were assessed by RNA sequencing. Data were analyzed with Ingenuity Pathways Analysis (QIAGEN Inc).

      Results

      Seven-day survival rate in septic mice was significantly improved in the H2 inhalation group compared with that in the control group (75% versus 40%, P < 0.05). H2 treatment attenuated serum interleukin-6 and tumor necrosis factor-α levels at 24 h after CLP, and blood glucose levels were maintained in the H2-treated group. In RNA sequencing, canonical pathway analysis revealed inactivity of various inflammatory signaling pathways, for example, acute phase response signaling and STAT3 pathways, in the liver and intestine in the CLP model after 24-h H2 inhalation. We detected significantly decreased expressions of upstream regulator genes such as the CD14 antigen gene in the liver and various cytokine receptor genes in the intestine and lungs in the H2-treated group.

      Conclusions

      These findings may contribute to clarifying the mechanism of action of H2 therapy in sepsis.

      Keywords

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