Dataset Information

Brain adaptation to hypoxia and hyperoxia in mice.

ABSTRACT:

Aims

Hyperoxic breathing might lead to redox imbalance and signaling changes that affect cerebral function. Paradoxically, hypoxic breathing is also believed to cause oxidative stress. Our aim is to dissect the cerebral tissue responses to altered O₂ fractions in breathed air by assessing the redox imbalance and the recruitment of the hypoxia signaling pathways.

Results

Mice were exposed to mild hypoxia (10%O₂), normoxia (21%O₂) or mild hyperoxia (30%O₂) for 28 days, sacrificed and brain tissue excised and analyzed. Although one might expect linear responses to %O₂, only few of the examined variables exhibited this pattern, including neuroprotective phospho- protein kinase B and the erythropoietin receptor. The major reactive oxygen species (ROS) source in brain, NADPH oxidase subunit 4 increased in hypoxia but not in hyperoxia, whereas neither affected nuclear factor (erythroid-derived 2)-like 2, a transcription factor that regulates the expression of antioxidant proteins. As a result of the delicate equilibrium between ROS generation and antioxidant defense, neuron apoptosis and cerebral tissue hydroperoxides increased in both 10%O₂ and 30%O₂, as compared with 21%O₂. Remarkably, the expression level of hypoxia-inducible factor (HIF)-2? (but not HIF-1?) was higher in both 10%O₂ and 30%O₂ with respect to 21%O₂ INNOVATION: Comparing the in vivo effects driven by mild hypoxia with those driven by mild hyperoxia helps addressing whether clinically relevant situations of O₂ excess and scarcity are toxic for the organism.

Conclusion

Prolonged mild hyperoxia leads to persistent cerebral damage, comparable to that inferred by prolonged mild hypoxia. The underlying mechanism appears related to a model whereby the imbalance between ROS generation and anti-ROS defense is similar, but occurs at higher levels in hypoxia than in hyperoxia.

SUBMITTER: Terraneo L

PROVIDER: S-EPMC5107733 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Publications

Brain adaptation to hypoxia and hyperoxia in mice.

Terraneo Laura L Paroni Rita R Bianciardi Paola P Giallongo Toniella T Carelli Stephana S Gorio Alfredo A Samaja Michele M

Redox biology 20161104

<h4>Aims</h4>Hyperoxic breathing might lead to redox imbalance and signaling changes that affect cerebral function. Paradoxically, hypoxic breathing is also believed to cause oxidative stress. Our aim is to dissect the cerebral tissue responses to altered O<sub>2</sub> fractions in breathed air by assessing the redox imbalance and the recruitment of the hypoxia signaling pathways.<h4>Results</h4>Mice were exposed to mild hypoxia (10%O<sub>2</sub>), normoxia (21%O<sub>2</sub>) or mild hyperoxia ( ...[more]

PMID: 27835780

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Project description:BackgroundNeonatal hyperoxia exposure is associated with brain injury and poor neurodevelopment outcomes in preterm infants. Our previous studies in neonatal rodent models have shown that hyperoxia stimulates the brain's inflammasome pathway, leading to the activation of gasdermin D (GSDMD), a key executor of pyroptotic inflammatory cell death. Moreover, we found pharmacological inhibition of caspase-1, which blocks GSDMD activation, attenuates hyperoxia-induced brain injury in neonatal mice. We hypothesized that GSDMD plays a pathogenic role in hyperoxia-induced neonatal brain injury and that GSDMD gene knockout (KO) will alleviate hyperoxia-induced brain injury.MethodsNewborn GSDMD knockout mice and their wildtype (WT) littermates were randomized within 24 h after birth to be exposed to room air or hyperoxia (85% O2) from postnatal days 1 to 14. Hippocampal brain inflammatory injury was assessed in brain sections by immunohistology for allograft inflammatory factor 1 (AIF1) and CD68, markers of microglial activation. Cell proliferation was evaluated by Ki-67 staining, and cell death was determined by TUNEL assay. RNA sequencing of the hippocampus was performed to identify the transcriptional effects of hyperoxia and GSDMD-KO, and qRT-PCR was performed to confirm some of the significantly regulated genes.ResultsHyperoxia-exposed WT mice had increased microglia consistent with activation, which was associated with decreased cell proliferation and increased cell death in the hippocampal area. Conversely, hyperoxia-exposed GSDMD-KO mice exhibited considerable resistance to hyperoxia as O2 exposure did not increase AIF1 + , CD68 + , or TUNEL + cell numbers or decrease cell proliferation. Hyperoxia exposure differentially regulated 258 genes in WT and only 16 in GSDMD-KO mice compared to room air-exposed WT and GSDMD-KO, respectively. Gene set enrichment analysis showed that in the WT brain, hyperoxia differentially regulated genes associated with neuronal and vascular development and differentiation, axonogenesis, glial cell differentiation, hypoxia-induced factor 1 pathway, and neuronal growth factor pathways. These changes were prevented by GSDMD-KO.ConclusionsGSDMD-KO alleviates hyperoxia-induced inflammatory injury, cell survival and death, and alterations of transcriptional gene expression of pathways involved in neuronal growth, development, and differentiation in the hippocampus of neonatal mice. This suggests that GSDMD plays a pathogenic role in preterm brain injury, and targeting GSDMD may be beneficial in preventing and treating brain injury and poor neurodevelopmental outcomes in preterm infants.

Project description:Understanding hypoxia/hyperoxia exposure requires either a high-altitude research facility or a chamber in which gas concentrations are precisely and reproducibly controlled. Hypoxia-induced conditions such as hypoxic-ischemic encephalopathy (HIE), obstructive or central apneas, and ischemic stroke present unique challenges for the development of models with acute or chronic hypoxia exposure. Many murine models exist to study these conditions; however, there are a variety of different hypoxia exposure protocols used across laboratories. Experimental equipment for hypoxia exposure typically includes flow regulators, nitrogen concentrators, and premix oxygen/nitrogen tanks. Commercial hypoxia/hyperoxia chambers with environmental monitoring are incredibly expensive and require proprietary software with subscription fees or highly expensive software licenses. Limitations exist in these systems as most are single animal systems and not designed for extended or intermittent hypoxia exposure. We have developed a simple hypoxia chamber with off-the-shelf components, and controlled by open-source software for continuous data acquisition of oxygen levels and other environmental factors (temperature, humidity, pressure, light, sound, etc.). Our chamber can accommodate up to two mouse cages and one rat cage at any oxygen level needed, when using a nitrogen concentrator or premixed oxygen/nitrogen tank with a flow regulator, but is also scalable. Our system uses a Python-based script to save data in a text file using modules from the sensor vendor. We utilized Python or R scripts for data analysis, and we have provided examples of data analysis scripts and acquired data for extended exposure periods (≤7 days). By using FLOS (Free-Libre and open-source) software and hardware, we have developed a low-cost and customizable system that can be used for a variety of exposure protocols. This hypoxia/hyperoxia exposure chamber allows for reproducible and transparent data acquisition and increased consistency with a high degree of customization for each experimenter's needs.

Dataset Information

Brain adaptation to hypoxia and hyperoxia in mice.

Aims

Results

Conclusion

Publications

Brain adaptation to hypoxia and hyperoxia in mice.

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