# H2 Inhibits the Formation of Neutrophil Extracellular Traps.
> 水素ガスは好中球細胞外トラップ（NET）の形成を抑制する


## Abstract

Neutrophil extracellular traps (NETs) are implicated in the pathogenesis of infectious and cardiovascular inflammatory conditions. This study examined whether H₂ exposure could suppress NET formation using neutrophils isolated from healthy human donors stimulated with PMA or the calcium ionophore A23187. H₂-exposed neutrophils showed reduced histone citrullination, chromatin-mediated membrane disruption, and NET component release compared with controls. H₂ also decreased Ser-139 phosphorylation of H2AX, a DNA damage marker, thereby lowering CXCR4 expression in NET-prone neutrophil subsets. Myeloperoxidase chlorination activity and reactive oxygen species production were suppressed to a degree comparable to N-acetylcysteine and ascorbic acid, yet H₂ demonstrated stronger NET inhibition than these antioxidants under PMA stimulation. For A23187-induced, ROS-independent NET formation, H₂ appeared to act through direct inhibition of peptidyl arginine deiminase 4 (PAD4)-mediated histone citrullination. In LPS-induced sepsis models (mice and aged mini pigs), H₂ inhalation reduced NET formation and component release in both blood and bronchoalveolar lavage fluid.

### Mechanism

H₂ inhibits NET formation by scavenging reactive oxygen species, suppressing myeloperoxidase chlorination activity, directly inhibiting PAD4-mediated histone citrullination, and reducing H2AX Ser-139 phosphorylation to downregulate CXCR4 expression in neutrophils.

## Bibliographic

- **Authors**: Shirakawa K, Kobayashi E, Ichihara G, Kitakata H, Katsumata Y, Sugai K, et al.
- **Journal**: JACC Basic Transl Sci
- **Year**: 2022
- **PMID**: [35257042](https://pubmed.ncbi.nlm.nih.gov/35257042/)
- **DOI**: [10.1016/j.jacbts.2021.11.005](https://doi.org/10.1016/j.jacbts.2021.11.005)
- **PMC**: [PMC8897170](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8897170/)
- **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 35257042. https://h2-papers.org/en/papers/35257042
> **Source**: PubMed PMID [35257042](https://pubmed.ncbi.nlm.nih.gov/35257042/)