# Molecular hydrogen inhibits lipopolysaccharide/interferon γ-induced nitric oxide production through modulation of signal transduction in macrophages.
> マクロファージにおける分子状水素のシグナル伝達調節を介したLPS/IFNγ誘導性一酸化窒素産生抑制


## Abstract

Using murine macrophage RAW264 cells, this study investigated how molecular hydrogen affects nitric oxide (NO) production stimulated by lipopolysaccharide and interferon-γ (LPS/IFNγ). Hydrogen exposure reduced NO release and diminished inducible nitric oxide synthase (iNOS) induction. Phosphorylation of apoptosis signal-regulating kinase 1 (ASK1) and its downstream effectors p38 MAP kinase and JNK, as well as IκBα, were all suppressed by hydrogen. Notably, NADPH oxidase activation and reactive oxygen species (ROS) generation remained unaffected. Because ROS normally activates ASK1, the ability of hydrogen to inhibit ASK1 without altering ROS levels points to a target molecule at or near the receptor level. In a separate in vivo experiment, oral administration of hydrogen-rich water reduced anti-type II collagen antibody-induced arthritis severity in mice, a model relevant to rheumatoid arthritis. These findings collectively position molecular hydrogen as a signal modulator that suppresses inflammatory NO production and highlight an interaction between NO and hydrogen as gaseous signaling molecules.

### Mechanism

Hydrogen inhibits ASK1 phosphorylation independently of ROS, thereby suppressing downstream p38 MAP kinase, JNK, and IκBα activation, which reduces iNOS induction and subsequent NO production in macrophages.

## Bibliographic

- **Authors**: Itoh T, Hamada N, Terazawa R, Ohno K, Ichihara M, Nozawa Y, et al.
- **Journal**: Biochem Biophys Res Commun
- **Year**: 2011 (2011-07-22)
- **PMID**: [21723254](https://pubmed.ncbi.nlm.nih.gov/21723254/)
- **DOI**: [10.1016/j.bbrc.2011.06.116](https://doi.org/10.1016/j.bbrc.2011.06.116)
- **Study type**: in vitro study
- **Delivery route**: mixed routes
- **Effect reported**: positive

## Delivery context

This study combines multiple delivery routes. As a general principle, the most efficient route for routine hydrogen intake is inhalation. Inhalation carries explosion risk (empirical LFL of 10%; high-concentration devices are documented in the Consumer Affairs Agency accident database and are not recommended).

## Safety notes

This study combines multiple delivery routes. As a general principle, the most efficient route for routine hydrogen intake is inhalation. Inhalation carries explosion risk (empirical LFL of 10%; high-concentration devices are documented in the Consumer Affairs Agency accident 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)
- [Inhalation safety threshold lineage](https://h2-papers.org/en/safety-notes/lineage)

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> **Cite as**: H2 Papers — PMID 21723254. https://h2-papers.org/en/papers/21723254
> **Source**: PubMed PMID [21723254](https://pubmed.ncbi.nlm.nih.gov/21723254/)