# Hydrogen Gas Protects Against Intestinal Injury in Wild Type But Not NRF2 Knockout Mice With Severe Sepsis by Regulating HO-1 and HMGB1 Release.
> 重症敗血症マウスにおける水素ガスの腸管保護効果：NRF2ノックアウトモデルによるHO-1およびHMGB1を介したメカニズムの解明


## Abstract

This animal study examined the intestinal effects of 2% H2 gas inhalation in a cecal ligation and puncture (CLP) model of severe sepsis, comparing wild-type (WT) and Nrf2 knockout (KO) mice. In WT animals, H2 inhalation improved 7-day survival, reduced pro-inflammatory cytokines (TNF-α, IL-6, HMGB1), elevated anti-inflammatory IL-10, enhanced antioxidant enzyme activity (superoxide dismutase, catalase), decreased oxidative markers (MDA, 8-iso-PGF2α), and upregulated heme oxygenase-1 (HO-1) expression in serum and intestinal tissue. These protective responses were absent in Nrf2 KO mice, indicating that the Nrf2 transcription factor is essential for H2-mediated intestinal protection. The findings suggest that HO-1 induction and HMGB1 suppression downstream of Nrf2 activation constitute the primary mechanism underlying H2 efficacy in sepsis-associated intestinal injury.

### Mechanism

H2 inhalation activates Nrf2, which upregulates HO-1 expression and suppresses HMGB1 release, thereby reducing oxidative stress and inflammatory damage in intestinal tissue. Deletion of Nrf2 abolishes these protective effects, confirming its essential role in the H2-mediated pathway.

## Bibliographic

- **Authors**: Yang Y, Bian Y, Li Y, Liu L, Zhang H, Xie K, et al.
- **Journal**: Shock
- **Year**: 2017
- **PMID**: [28234792](https://pubmed.ncbi.nlm.nih.gov/28234792/)
- **DOI**: [10.1097/SHK.0000000000000856](https://doi.org/10.1097/SHK.0000000000000856)
- **Study type**: animal study
- **Delivery route**: inhalation
- **Effect reported**: positive
- **H2 concentration**: 2%

## Delivery context

For inhalation applications of molecular hydrogen, the lower flammability limit (LFL) deserves careful handling. The classical 4% figure applies to closed-system mixtures; the practical inhalation-environment threshold is 10%. Even pure-hydrogen output (the UFL 75% paradox) passes through the flammable range at the air–gas boundary. High-concentration (66% / 100%) inhalers are documented in the Japanese Consumer Affairs Agency accident-information database and are not recommended.

## Safety notes

For inhalation applications of molecular hydrogen, the lower flammability limit (LFL) deserves careful handling. The classical 4% figure applies to closed-system mixtures; the practical inhalation-environment threshold is 10%. Even pure-hydrogen output (the UFL 75% paradox) passes through the flammable range at the air–gas boundary. High-concentration (66% / 100%) inhalers are documented in the Japanese Consumer Affairs Agency accident-information database and are not recommended.

See also:
- [Inhalation concentration and LFL / UFL](https://h2-papers.org/en/safety-notes/inhalation-concentration)
- [Consumer Affairs Agency accident cases](https://h2-papers.org/en/safety-notes/accident-cases)
- [LFL / UFL terminology](https://h2-papers.org/en/safety-notes/lfl-ufl-explained)
- [Inhalation safety threshold lineage](https://h2-papers.org/en/safety-notes/lineage)

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> **Cite as**: H2 Papers — PMID 28234792. https://h2-papers.org/en/papers/28234792
> **Source**: PubMed PMID [28234792](https://pubmed.ncbi.nlm.nih.gov/28234792/)