Molecular hydrogen attenuates sepsis-induced neuroinflammation through regulation of microglia polarization through an mTOR-autophagy-dependent pathway.
mTOR-オートファジー経路を介したミクログリア極性化制御による分子状水素の敗血症関連神経炎症抑制効果
Abstract
Sepsis-associated encephalopathy (SAE) causes cognitive dysfunction and elevates morbidity and mortality. Using a cecal ligation and puncture (CLP) mouse model alongside LPS-stimulated BV-2 microglial cells, this study examined how hydrogen inhalation affects SAE and its underlying mechanism. In vivo, hydrogen inhalation improved Morris Water Maze performance, including escape latency and platform-crossing frequency. Both animal and cell experiments showed reductions in TNF-α, IL-6, and HMGB1, alongside increases in IL-10 and TGF-β. M1 microglia polarization was suppressed while M2 polarization was enhanced. In BV-2 cells, hydrogen decreased the p-mTOR/mTOR and p62 levels while increasing p-AMPK/AMPK and LC3II/LC3I ratios, as well as TREM-2 and Beclin-1 expression. Application of the mTOR activator MHY1485 abolished these protective effects, confirming that the mTOR-autophagy pathway mediates hydrogen's anti-neuroinflammatory actions.
Mechanism
Hydrogen activates AMPK and suppresses mTOR, thereby promoting autophagy (elevated LC3II/LC3I and Beclin-1, reduced p62), which drives microglial polarization from the pro-inflammatory M1 phenotype toward the anti-inflammatory M2 phenotype, reducing neuroinflammatory cytokine release.
Bibliographic
- Authors
- Zhuang X, Jiang Y, Zhao S, Wang Y, Su L, Xie K, et al.
- Journal
- Int Immunopharmacol
- Year
- 2020
- PMID
- 32058932
- DOI
- 10.1016/j.intimp.2020.106287
Tags
Delivery context
In air, molecular hydrogen is reported to be combustible across approximately **4% (LFL, lower flammability limit) to 75% (UFL, upper flammability limit)**. Among high-concentration hydrogen inhalers, 66% output sits inside this range, and even pure-hydrogen (100%) output forms a 4–75% concentration-gradient layer at the device–air boundary (the UFL 75% paradox). Engineering principle would therefore call for operation below LFL (the classical 4%); that figure, however, was measured under closed, pre-mixed, static conditions. For the open, dynamic inhalation environment, the empirical value reported in the literature is **10%**, which is the figure referenced in practice as the operating ceiling. The 66% / 100% output devices are recorded in the Japanese Consumer Affairs Agency accident-information database, and from these considerations are not recommended.
Safety notes
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