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Hydrogen inhalation attenuates mechanical ventilation-induced postoperative cognitive dysfunction in aged mice by inhibiting the lung–brain axis-mediated transmission of pTau217-enriched extracellular vesicles
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DOI：10.1186/s12974-026-03985-y.png)
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Abstract
En 中文
Mechanical ventilation (MV) is an indispensable respiratory support strategy; however, increasing evidence suggests it may be a primary mediator of postoperative cognitive dysfunction (POCD) in vulnerable elderly patients. Despite this potential association, the precise lung–brain mechanisms through which MV-induced pulmonary stress mediates cognitive impairment and neurodegeneration remain unclear. To elucidate this interorgan cross-talk, we first conducted an observational analysis of plasma extracellular vesicles (EVs) from elderly surgical patients. We identified an association of general anesthesia, surgery, and MV with a marked postoperative increase in circulating EV-derived pTau217 levels, accompanied by a proteomic signature enriched in lung-related markers. In an aged murine MV model, we mapped the rapid lung-to-brain trajectory of pTau217-enriched extracellular vesicles (0–6 h) and subsequent microglial activation and cognitive impairment. The results of integrated scRNA-seq and metabolomic profiling revealed that these EVs originated from bronchial epithelial cells, suggesting severe metabolic disturbance. The inhalation of hydrogen (H2) effectively averted this metabolic crisis, thereby inhibiting local Tau hyperphosphorylation and halting the release of pTau217-enriched EVs. This upstream blockade subsequently prevented microglial activation and rescued cognitive performance. These findings define a pathological lung–brain axis in which MV-induced metabolic disruption drives the EV-mediated spread of pTau217 to precipitate POCD in aged mice. Importantly, H2 therapy restores pulmonary metabolic homeostasis to halt this transmission at its source, suggesting a potential targeted intervention to preserve the aging brain in the perioperative period.
Keywords:
Postoperative cognitive dysfunction
pTau217
Exosomes
Lung–brain axis
Hydrogen
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