Effects of Acute Systemic Hypoxia and Hypercapnia on Brain Damage in a Rat Model of Hypoxia-Ischemia

Yang, Wanchao; Zhang, Xuezhong; Wang, Nan; Tan, Jing; Fang, Xianhai; Wang, Qi; Tao, Tao; Li, Wenzhi

doi:10.1371/journal.pone.0167359

Cited by 26 publications

(24 citation statements)

References 42 publications

(45 reference statements)

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“…This could account for why there is currently little consensus regarding whether AQP4 changes in expression levels is upregulated in animal models of stroke, as variations in the stroke model, the duration of reperfusion, and the methods used to determine AQP4 levels can all affect the outcome. For instance, it was observed in a recent study that, while AQP4 protein levels in the cortex are elevated by increasing levels of hypoxia, the effect is exacerbated by additional hypercapnia only in the animals that have undergone the more severe oxygen-deprivation treatments; paradoxically, CO 2 caused a decrease in AQP4 expression in animals given air containing a near-normal amount of oxygen (Yang et al, 2016 ). Oxidative stress probably elicits a similarly graded response, the consequences of which may be therapeutically relevant.…”

Section: Discussionmentioning

confidence: 99%

The Oxidative Stress-Induced Increase in the Membrane Expression of the Water-Permeable Channel Aquaporin-4 in Astrocytes Is Regulated by Caveolin-1 Phosphorylation

Tham

Perronnet

et al. 2017

Front. Cell. Neurosci.

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The reperfusion of ischemic brain tissue following a cerebral stroke causes oxidative stress, and leads to the generation of reactive oxygen species (ROS). Apart from inflicting oxidative damage, the latter may also trigger the upregulation of aquaporin 4 (AQP4), a water-permeable channel expressed by astroglial cells of the blood-brain barrier (BBB), and contribute to edema formation, the severity of which is known to be the primary determinant of mortality and morbidity. The mechanism through which this occurs remains unknown. In the present study, we have attempted to address this question using primary astrocyte cultures treated with hydrogen peroxide (H2O2) as a model system. First, we showed that H2O2 induces a significant increase in AQP4 protein levels and that this is inhibited by the antioxidant N-acetylcysteine (NAC). Second, we demonstrated using cell surface biotinylation that H2O2 increases AQP4 cell-surface expression independently of it’s increased synthesis. In parallel, we found that caveolin-1 (Cav1) is phosphorylated in response to H2O2 and that this is reversed by the Src kinase inhibitor 4-Amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2). PP2 also abrogated the H2O2-induced increase in AQP4 surface levels, suggesting that the phosphorylation of tyrosine-14 of Cav1 regulates this process. We further showed that dominant-negative Y14F and phosphomimetic Y14D mutants caused a decrease and increase in AQP4 membrane expression respectively, and that the knockdown of Cav1 inhibits the increase in AQP4 cell-surface, expression following H2O2 treatment. Together, these findings suggest that oxidative stress-induced Cav1 phosphorylation modulates AQP4 subcellular distribution and therefore may indirectly regulate AQP4-mediated water transport.

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Section: Discussionmentioning

confidence: 99%

The Oxidative Stress-Induced Increase in the Membrane Expression of the Water-Permeable Channel Aquaporin-4 in Astrocytes Is Regulated by Caveolin-1 Phosphorylation

Tham

Perronnet

et al. 2017

Front. Cell. Neurosci.

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“…no.1063180500) and were mechanically ventilated for 3 h using a small-animal ventilator (SAR-1000, CWE, Ardmore, PA, USA). The tidal volume was set at 9 ml/kg body weight, the respiratory rate was 45 breaths/min, and inspiratory to expiratory ratio was 1:1 [ 22 ]. Mechanical ventilation was performed using a gas tank containing either room air (S group), a gas mixture containing 5% CO 2 , 21% O 2 , 74% N 2 (Hypercapnia group), 16% O 2 , 84% N 2 (Hypoxemia group), or 5% CO 2 , 16% O 2 , and 79% N 2 (HH group).…”

Section: Methodsmentioning

confidence: 99%

Hypercapnia induces IL-1β overproduction via activation of NLRP3 inflammasome: implication in cognitive impairment in hypoxemic adult rats

Ding

Deng

Yang

et al. 2018

J Neuroinflammation

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BackgroundCognitive impairment is one of common complications of acute respiratory distress syndrome (ARDS). Increasing evidence suggests that interleukin-1 beta (IL-1β) plays a role in inducing neuronal apoptosis in cognitive dysfunction. The lung protective ventilatory strategies, which serve to reduce pulmonary morbidity for ARDS patients, almost always lead to hypercapnia. Some studies have reported that hypercapnia contributes to the risk of cognitive impairment and IL-1β secretion outside the central nervous system (CNS). However, the underlying mechanism of hypercapnia aggravating cognitive impairment under hypoxia has remained uncertain. This study was aimed to explore whether hypercapnia would partake in increasing IL-1β secretion via activating the NLRP3 (NLR family, pyrin domain-containing 3) inflammasome in the hypoxic CNS and in aggravating cognitive impairment.MethodsThe Sprague-Dawley (SD) rats that underwent hypercapnia/hypoxemia were used for assessment of NLRP3, caspase-1, IL-1β, Bcl-2, Bax, and caspase-3 expression by Western blotting or double immunofluorescence, and the model was also used for Morris water maze test. In addition, Z-YVAD-FMK, a caspase-1 inhibitor, was used to treat BV-2 microglia to determine whether activation of NLRP3 inflammasome was required for the enhancing effect of hypercapnia on expressing IL-1β by Western blotting or double immunofluorescence. The interaction effects were analyzed by factorial ANOVA. Simple effects analyses were performed when an interaction was observed.ResultsThere were interaction effects on cognitive impairment, apoptosis of hippocampal neurons, activation of NLRP3 inflammasome, and upregulation of IL-1β between hypercapnia treatment and hypoxia treatment. Hypercapnia + hypoxia treatment caused more serious damage to the learning and memory of rats than those subjected to hypoxia treatment alone. Expression levels of Bcl-2 were reduced, while that of Bax and caspase-3 were increased by hypercapnia in hypoxic hippocampus. Hypercapnia markedly increased the expression of NLRP3, caspase-1, and IL-1β in hypoxia-activated microglia both in vivo and in vitro. Pharmacological inhibition of NLRP3 inflammasome activation and release of IL-1β might ameliorate apoptosis of neurons.ConclusionsThe present results suggest that hypercapnia-induced IL-1β overproduction via activating the NLRP3 inflammasome by hypoxia-activated microglia may augment neuroinflammation, increase neuronal cell death, and contribute to the pathogenesis of cognitive impairments.

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“…[18][19][20] In our previous study, hypercapnia exerted bene cial effects under mild to moderate hypoxemia and augmented the detrimental effects on the brain during severe hypoxemia in a rat model of hypoxiaischemia. [7] However, BBB dysfunction did not further deteriorate after combined exposure to moderate hypoxia and hypercapnia in this animal model. Moreover, little is known about how the hypercapnia affects molecular and functional changes, such as hypoxia-induced disruption of the TJs, in BBB dysfunction.…”

mentioning

confidence: 61%

“…In our previous study, our ndings suggested that the addition of hypercapnia aggravated the injury after CCA ligation along with severe hypoxemia (PaO 2 < 50 mmHg), but hypercapnia produced protective effects against HIinduced brain damage in rats treated with mild to moderate systemic hypoxia (15% and 18% O 2 , PaO 2 > 50 mmHg). [7] It is possible that the severe injury exceeded the short-term therapeutic potential of exposure to hypercapnia gas. The large volume of ischemic tissue may have overwhelmed any possible bene t of hypercapnia gas exposure.…”

Section: Discussionmentioning

confidence: 99%

Neuroprotection by hypercapnia in brain ischemic injury followed by persistent hypoxia: an in vivo and in vitro experimental study

Yang¹,

Wang²,

Wu³

et al. 2020

Preprint

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Backgrounds: Therapeutic hypercapnia was shown to have a potential neuroprotective role in our previous studies in a rat model of ischemia followed by hypoxia; however, it is unknown how hypercapnia affects blood-brain barrier (BBB) function under hypoxic conditions in cerebral ischemia. We aimed to observe the BBB permeability changes in response to cerebral ischemia followed by acute hypoxia or hypercapnic hypoxia using in vivo and in vitro models.Methods: Adult rats underwent unilateral common carotid artery ligation, at 60 min of ligation, they were exposed to systemic hypoxia with ventilation of 15% oxygen (O2) combined with 8% carbon dioxide (CO2) for 180 min. Cerebral blood flow, BBB integrity, infarct volume and behavior were assessed in this study. In vitro, rat brain microvascular endothelial cells (BMECs) were isolated and cultured under O2 (1% or 21%) with or without 15% CO2 for 6 h. Cell viability and transendothelial electrical resistance (TEER) were measured. The ZO-1 and occludin protein levels were explored in BMECs by Western blotting.Results: Arterial blood O2 (PaO2) tensions averaged 56.1 mmHg during simple hypoxia, and arterial blood CO2 tensions (PaCO2) were maintained at normal values or 60–80 mmHg. Hypercapnia treatment significantly reduced brain infarct volume and pathophysiological changes in hypoxic ischemia rats. Furthermore, in the in vitro experiment, hypercapnia significantly improved the growth condition of BMECs, reduced endothelial cell permeability and attenuated the loss of ZO-1 and occludin protein in BMECs induced by hypoxia. Conclusions: Hypercapnia exerts beneficial effects on the BBB permeability in the rat model of hypoxic-ischemic injury and recovers the neurologic status especially within one week, possibly by preventing the loss of tight junction proteins.

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Effects of Acute Systemic Hypoxia and Hypercapnia on Brain Damage in a Rat Model of Hypoxia-Ischemia

Cited by 26 publications

References 42 publications

The Oxidative Stress-Induced Increase in the Membrane Expression of the Water-Permeable Channel Aquaporin-4 in Astrocytes Is Regulated by Caveolin-1 Phosphorylation

The Oxidative Stress-Induced Increase in the Membrane Expression of the Water-Permeable Channel Aquaporin-4 in Astrocytes Is Regulated by Caveolin-1 Phosphorylation

Hypercapnia induces IL-1β overproduction via activation of NLRP3 inflammasome: implication in cognitive impairment in hypoxemic adult rats

Neuroprotection by hypercapnia in brain ischemic injury followed by persistent hypoxia: an in vivo and in vitro experimental study

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