H₂ Papers

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Hydrogen gas alleviates blood-brain barrier impairment and cognitive dysfunction of septic mice in an Nrf2-dependent pathway.

Nrf2依存的経路を介した水素ガスによる敗血症マウスの血液脳関門障害および認知機能障害の軽減

animal study inhalation positive 2%

Abstract

Sepsis-associated encephalopathy (SAE) involves blood-brain barrier (BBB) disruption leading to cognitive impairment and elevated mortality. Using a cecal ligation and puncture (CLP) model in female wild-type and Nrf2-knockout C57BL/6J mice, this study examined whether 2% H2 inhalation (60 min at 1 h and 6 h post-CLP) could protect the BBB via Nrf2 signaling. In wild-type animals, H2 improved 7-day survival, reduced escape latency in the Morris water maze, lowered cortical levels of TNF-α, IL-6, HMGB1, MDA, and 8-iso-PGF2α, and elevated IL-10, SOD, and CAT. BBB integrity markers—ZO-1 and VE-cadherin—were upregulated, while brain water content, Evans blue extravasation, and dextran leakage decreased. β-catenin phosphorylation was also modulated. None of these effects were observed in Nrf2-knockout mice or in bEnd.3 cells treated with the Nrf2 inhibitor ML385, confirming that Nrf2 and its downstream antioxidant pathways are required for H2-mediated BBB preservation and cognitive protection in sepsis.

Mechanism

H2 activates Nrf2 and its downstream antioxidant pathways, suppressing pro-inflammatory cytokines and oxidative stress markers, thereby reducing BBB permeability and preserving tight junction proteins ZO-1 and VE-cadherin in septic brain tissue.

Bibliographic

Authors
Feng J, Lian N, Yang M, Xie K, Wang G, Wang CY, et al.
Journal
Int Immunopharmacol
Year
2020
PMID
32447221
DOI
10.1016/j.intimp.2020.106585

Tags

Disease:cognitive decline (111) sepsis (48) Delivery:inhalation delivery (196) Mechanism:antioxidant enzymes (423) anti-inflammatory (743) Nrf2 pathway (106) oxidative stress (899) reactive oxygen species (774)

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.

→ Evidence by delivery route

Safety notes

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.

See also:

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