Improved Neuroimaging Findings and Cognitive Function in a Case of High-altitude Cerebral Edema

Urushida, Yuki; Kikuchi, Yutaro; Shimizu, Chisato; Amari, Masakuni; Kawarabayashi, Tatsuhiko; Nakamura, Takumi; Ikeda, Yoshio; Takatama, Masamitsu; Shoji, Mikio

doi:10.2169/internalmedicine.5747-20

Cited by 8 publications

(9 citation statements)

References 11 publications

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“…Significant vascular leakage near the corpus callosum and diffusion of microleakage in the mouse cerebral cortex were observed in our HACE model, which is consistent with the MRI findings in HACE patients [9 , 10] . The degradation of endothelial cell TJs can lead to the extravasation of plasma proteins and water, triggering vasogenic edema.…”

Section: Discussionsupporting

confidence: 90%

“…Magnetic resonance imaging (MRI) data from HACE patients showed marked brain edema with microvascular haemorrhages in the corpus callosum and white matter areas, accompanied by cytotoxic and vasogenic edema [9 , 10] . Clinical and animal studies have demonstrated that vasogenic edema induced by cerebral microvascular rupture due to blood‒brain barrier (BBB) injury is considered the leading cause of HACE [11 – 13] .…”

Section: Introductionmentioning

confidence: 99%

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Caveolin-1 accelerates hypoxia-induced endothelial dysfunction in high-altitude cerebral edema

et al. 2022

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Background High-altitude cerebral edema (HACE) is a serious and potentially fatal brain injury that is caused by acute hypobaric hypoxia (HH) exposure. Vasogenic edema is the main pathological factor of this condition. Hypoxia-induced disruptions of tight junctions in the endothelium trigger blood‒brain barrier (BBB) damage and induce vasogenic edema. Nuclear respiratory factor 1 (NRF1) acts as a major regulator of hypoxia-induced endothelial cell injury, and caveolin-1 (CAV-1) is upregulated as its downstream gene in hypoxic endothelial cells. This study aimed to investigate whether CAV-1 is involved in HACE progression and the underlying mechanism. Methods C57BL/6 mice were exposed to HH (7600 m above sea level) for 24 h, and BBB injury was assessed by brain water content, Evans blue staining and FITC-dextran leakage. Immunofluorescence, transmission electron microscope, transendothelial electrical resistance (TEER), transcytosis assays, and western blotting were performed to confirm the role and underlying mechanism of CAV-1 in the disruption of tight junctions and BBB permeability. Mice or bEnd.3 cells were pretreated with MβCD, a specific blocker of CAV-1, and the effect of CAV-1 on claudin-5 internalization under hypoxic conditions was detected by immunofluorescence, western blotting, and TEER. The expression of NRF1 was knocked down, and the regulation of CAV-1 by NRF1 under hypoxic conditions was examined by qPCR, western blotting, and immunofluorescence. Results The BBB was severely damaged and was accompanied by a significant loss of vascular tight junction proteins in HACE mice. CAV-1 was significantly upregulated in endothelial cells, and claudin-5 explicitly colocalized with CAV-1. During the in vitro experiments, hypoxia increased cell permeability, CAV-1 expression, and claudin-5 internalization and downregulated tight junction proteins. Simultaneously, hypoxia induced the upregulation of CAV-1 by activating NRF1. Blocking CAV-1-mediated intracellular transport improved the integrity of TJs in hypoxic endothelial cells and effectively inhibited the increase in BBB permeability and brain water content in HH animals. Conclusions Hypoxia upregulated CAV-1 transcription via the activation of NRF1 in endothelial cells, thus inducing the internalization and autophagic degradation of claudin-5. These effects lead to the destruction of the BBB and trigger HACE. Therefore, CAV-1 may be a potential therapeutic target for HACE.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Caveolin-1 accelerates hypoxia-induced endothelial dysfunction in high-altitude cerebral edema

et al. 2022

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“…The addition of LPS altered the conditions under which brain edema is induced. It was observed in our study that HACE was induced in mice exposed to 7000 m above sea level for 48 h, and Evens blue imaging results revealed vascular leakage near the corpus callosum, which is consistent with the onset and symptoms of HACE in humans ( Hackett, 1999 ; Urushida et al., 2021 ).…”

Section: Discussionsupporting

confidence: 88%

“…HACE is characterized by brain edema and high intracranial pressure ( Hackett, 1999 ; Urushida et al., 2021 ). Magnetic resonance (MR) imaging research in HACE patients suggests edema in the white matter corpus callosum rather than in the gray matter, leading to a hypothesis about the vasogenic origin for the edema ( Hackett, 1999 ).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, hypoxia triggers a pro-inflammatory response in microglia, which benefits astrocyte swelling by up-regulating aquaporin 4 (AQP4), the hallmark protein of cytotoxic edema in HACE ( Wang et al., 2018 ; Zhao et al., 2018 ). Based on the existence of both vascular edema and cytotoxic edema in HACE ( Hackett, 1999 ; Kallenberg et al., 2007 ; Zhou et al., 2017 ; Urushida et al., 2021 ), we speculate that over-activation of microglia triggers AMS progressing to HACE.…”

Section: Introductionmentioning

confidence: 90%

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NRF1-mediated microglial activation triggers high-altitude cerebral edema

Wang

Chen

Wan

et al. 2022

Journal of Molecular Cell Biology

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High-altitude cerebral edema (HACE) is a potentially fatal encephalopathy associated with a time-dependent exposure to the hypobaric hypoxia of altitude. The formation of HACE is affected by both vasogenic and cytotoxic edema. The over-activated microglia potentiate the damage of blood–brain barrier (BBB) and exacerbate cytotoxic edema. In light with the activation of microglia in HACE, we aimed to investigate whether the over-activated microglia were the key turning point of acute mountain sickness to HACE. In in vivo experiments, by exposing mice to hypobaric hypoxia (7000 m above sea level) to induce HACE model, we found that microglia were activated and migrated to blood vessels. Microglia depletion by PLX5622 obviously relieved brain edema. In in vitro experiments, we found that hypoxia induced cultured microglial activation, leading to the destruction of endothelial tight junction and astrocyte swelling. Up-regulated nuclear respiratory factor 1 (NRF1) accelerated pro-inflammatory factors through transcriptional regulation on nuclear factor kappa B p65 (NF-κB p65) and mitochondrial transcription factor A (TFAM) in activated microglia under hypoxia. NRF1 also up-regulated phagocytosis by transcriptional regulation on caveolin-1 (CAV-1) and adaptor-related protein complex 2 subunit beta (AP2B1). The present study reveals a new mechanism in HACE: hypoxia over activates microglia through up-regulation of NRF1, which both induces inflammatory response through transcriptionally activating NF-κB p65 and TFAM, and enhances phagocytic function through up-regulation of CAV-1 and AP2B1; hypoxia-activated microglia destroy the integrity of BBB and release pro-inflammatory factors that eventually induce HACE.

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Protective effect of 5,6,7,8-Tetrahydroxyflavone on high altitude cerebral edema in rats

Jing

Zhang

et al. 2022

European Journal of Pharmacology

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Improved Neuroimaging Findings and Cognitive Function in a Case of High-altitude Cerebral Edema

Cited by 8 publications

References 11 publications

Caveolin-1 accelerates hypoxia-induced endothelial dysfunction in high-altitude cerebral edema

Caveolin-1 accelerates hypoxia-induced endothelial dysfunction in high-altitude cerebral edema

NRF1-mediated microglial activation triggers high-altitude cerebral edema

Protective effect of 5,6,7,8-Tetrahydroxyflavone on high altitude cerebral edema in rats

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