Evidence map›Paper›PMID 41981595›Full record

ArticleJournal of neuroinflammation2026

Neonatal sevoflurane exposure disrupts the lung-brain axis and drives microglial neuroinflammation and cognitive deficits.

Lirong Liang, Shuhui Cao, Youyi Zhao, Bing Liu, Jiachen Wang, Peiqin Gong, Yifei Wang, Guanghui Hao, Xingchen ZhangMu, Naining Lu and 4 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of neuroinflammation, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed.

  1. Article
  2. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

14 authors.

Lirong Liang *Department of Anesthesiology, State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, P. R. China.
Shuhui Cao *Department of Anesthesiology and Perioperative Medicine, Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center for Anesthesiology and Perioperative Medicine, Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, 200434, China.
Youyi ZhaoDepartment of Anesthesiology, State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, P. R. China.
Bing LiuDepartment of Anesthesiology, State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, P. R. China.
Jiachen WangDepartment of Anesthesiology, State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, P. R. China.
Peiqin GongDepartment of Anesthesiology, State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, P. R. China.
Yifei WangDepartment of Anesthesiology, State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, P. R. China.
Guanghui HaoDepartment of Anesthesiology, State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, P. R. China.
Xingchen ZhangMuDepartment of Anesthesiology, State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, P. R. China.
Naining LuDepartment of Neurobiology and Institute of Neurosciences, School of Basic Medicine, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, P. R. China.
Haopeng ZhangDepartment of Anesthesiology, State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, P. R. China. haopeng.zhang@foxmail.com.
Shengxi WuDepartment of Neurobiology and Institute of Neurosciences, School of Basic Medicine, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, P. R. China. shengxi@fmmu.edu.cn.
Fang KuangDepartment of Neurobiology and Institute of Neurosciences, School of Basic Medicine, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, P. R. China. kuangf@fmmu.edu.cn.
Hui ZhangDepartment of Anesthesiology, State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, P. R. China. zhanghuifmmua@163.com.

Funding

National Natural Science Foundation of China 82101345National Natural Science Foundation of China 82171170National Natural Science Foundation of China 82201414National Natural Science Foundation of China 82271231Science and Technology Plan in Xi'an of China 25YXYJYB00143
6 · The paper itself

Abstract

backgroundNeonatal sevoflurane exposure in mice induces microglial activation and long-term cognitive deficits, a finding that raises significant concerns for pediatric anesthesia. The lung-brain axis, a critical pathway mediating pulmonary-central nervous system communication, is indispensable for maintaining organismal homeostasis. However, existing research on anesthetic neurotoxicity has focused predominantly on central mechanisms, with insufficient attention to the lung-a major immune organ with extensive bidirectional crosstalk with the brain. Herein, we aim to explore the lung-brain interactions underlying long-term cognitive sequelae of neonatal sevoflurane exposure.

methodsC57BL/6J mice were selected and exposed to 3% sevoflurane for 2 h daily on postnatal days 6-8. Upon reaching adulthood, cognitive function and microglial activation status were evaluated. At 4 weeks post-exposure, 16S rRNA gene sequencing and metabolomic analysis were performed respectively to characterize the structure of the pulmonary microbiota and the metabolite profile. Proximity ligation assay (PLA), fluorescence lifetime imaging microscopy-fluorescence resonance energy transfer (FLIM-FRET), and co-immunoprecipitation (COIP) were employed to investigate the molecular mechanisms by which lung-derived metabolites mediate brain effects. Additionally, rescue experiments were conducted by administering the sphingosine-1-phosphate receptor modulator FTY720 and Moce to validate the aforementioned effects.

resultsRepeated neonatal sevoflurane exposure impaired adult cognitive function, induced microglial activation, and was concurrent with pulmonary microbiome dysbiosis and metabolic alterations. Notably, sphingosine-a key membrane lipid-was significantly decreased. Intratracheal administration of FTY720, a sphingosine analog, alleviated neuroinflammation and ameliorated cognitive deficits. Mechanistically, sevoflurane exposure upregulated HDAC1 and downregulated KLF4, whereas FTY720 significantly rescued these sevoflurane-induced expression aberrations, implicating the HDAC1/KLF4 axis in the regulation of neuroinflammation. Additionally, MOCE significantly alleviated neuroinflammation and ameliorated cognitive deficits.

conclusionsDevelopmental sevoflurane exposure induces microglial activation and cognitive decline via a pulmonary dysbiosis-sphingosine reduction cascade. The sphingosine-1-phosphate receptor modulator FTY720 mitigates this impairment by regulating microglial activation and neuroinflammation. These findings reveal novel mechanisms of anesthetic neurotoxicity and identify potential neuroprotective targets for pediatric anesthesia.

Indexed as

Anesthetics, InhalationBrainCognitive DysfunctionLungMicrogliaNeuroinflammatory DiseasesSevofluraneAnimalsAnimals, NewbornMaleMiceMice, Inbred C57BLAnesthetics, InhalationSevofluraneDevelopment brainLung-brain axisMicrogliaSevofluraneSphingosine

Identifiers

PMID41981595
PMCPMC13200307

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.