Hypoxic Exposure Research Articles

Effect of elastin on abnormal proliferation of pulmonary artery smooth muscle cells at an early stage of hypoxic exposure

Elastin (Eln) is an extracellular matrix protein implicated in the proliferation of vascular smooth muscle cells. However, its potential role in hypoxic pulmonary hypertension (HPH) remains uncertain. This study is the first to demonstrate that elastin can promote the proliferation of mouse pulmonary artery smooth muscle cells (mPASMCs) and that hypoxia significantly induces Eln expression in cultured mPASMCs, thereby participating in the cell cycle. Interference with Eln expression via siRNA led to the downregulation of PCNA, Cyclin A, and Cyclin D, thus, the hypoxia-induced proliferation of mPASMCs was reversed. Furthermore, our study demonstrated that the hypoxia-induced expression of Eln and the proliferation of mPASMCs are associated with the proliferation-related phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. In conclusion, these data suggest that Eln is a key regulatory factor in mPASMCs proliferation, potentially elucidating the mechanism underlying hypoxia-induced mPASMCs proliferation. This finding may offer valuable insights for the study of hypoxic pulmonary hypertension.

Activation of LXR signaling ameliorates apoptosis of alveolar epithelial cells in Bronchopulmonary dysplasia

Background and purposesLiver X receptors (LXRs) are specialized nuclear receptors essential for maintaining cholesterol homeostasis, modulating LXR activity could have therapeutic potential in lung diseases. Bronchopulmonary dysplasia (BPD) is a chronic lung disease characterized by impaired alveolar development, in which apoptosis of alveolar epithelial cells is a key contributing factor. The current research focuses on exploring the potential mechanism by which the LXR pathway regulating alveolar epithelial type II cell apoptosis in response to hyperoxia exposure.MethodsBPD infants and non-BPD preterm infants were enrolled to measure serum total cholesterol (TC) levels. To further investigate the role of cholesterol metabolism in BPD, a neonatal rat model of BPD was established, and in vitro studies were conducted using mouse lung epithelial cells (MLE12). These experiments aimed to explore the impact of hyperoxia on cholesterol metabolism and assess the effects of LXR agonist intervention.ResultsElevated serum TC levels in BPD infants were observed, accompanied by lung cholesterol overload in BPD rats. Hyperoxia exposure also led to intracellular cholesterol accumulation in MLE12 cells, which may be attributed to the downregulated LXR signaling pathway. Activation of the LXR pathway prevented apoptosis and mitochondrial dysfunction in MLE12 cell. In BPD rats, intervention with the LXR agonist restored alveolar architecture and reduced alveolar epithelial type II cell apoptosis, which was associated with decreased oxidative stress and lung cholesterol accumulation.ConclusionsDisrupted cholesterol metabolism and impaired homeostasis in premature infants may contribute to the development of BPD. Targeting LXR signaling may provide potential therapeutic targets in BPD.Clinical trial numberNot applicable.

High-altitude hypoxia exposure alters follicular metabolome and oocyte developmental potential in women.

To explore the effects of high-altitude hypoxia on the microenvironment of oocyte development and fertilization potential, we compared the metabolomic patterns of follicular fluid from women living in different altitude areas and traced their oocyte maturation and subsequent development. A total of 315 clinical cases were collected and divided into three groups according to their residence altitudes: 138 cases in low-altitude (< 2300m) group, 100 cases in middle-altitude (2300-2800m) group and 77 cases in high-altitude (> 2800m) group. The clinical outcomes were statistically estimated, including hormonal level, oocyte maturation, in vitro fertilization, and embryo development. Meanwhile, a metabolomic analysis was performed on the follicular fluid of women from different groups using ultra-high-performance liquid chromatography and high-resolution mass spectrometry and differential metabolites were analyzed through the KEGG pathway. The clinical data indicated that the physical condition and reproductive hormone secretion were similar among different groups. Although personalized gonadotropin-releasing hormone strategies were applied, the numbers of antral follicles and obtained oocytes were not impacted by the residence altitude change. In in vitro culture, the maturing rate, fertility rate and cleavage rate of high-altitude group were compared with the other groups. However, the rates of high-quality embryo, formative blastocyst, and available blastocyst were gradually decreased with the rise of residence altitude. Metabolome analysis identified 1193 metabolites in female follicular fluid. Differential analysis indicated that metabolic components in follicular fluid were remarkably changed with the elevation of residence altitude. These differential metabolites were closely related with amino acid metabolism, protein digestion and absorption, oocyte meiosis and steroid biosynthesis. The residence altitude alters the microenvironment of follicular fluid, which could damage the oocyte developmental potential. This study provides diagnostic basis and therapeutic targets for research on female oocyte and embryo development.

Alveolarization is Impaired by Maternal Selenium Deficiency and Exacerbated by Hyperoxia Exposure

Alveolarization is Impaired by Maternal Selenium Deficiency and Exacerbated by Hyperoxia Exposure

Fipronil exposure alters oxidative stress responses of Nile tilapia (Oreochromis niloticus) to acute moderate hypoxia

Acute hypoxia is known to increase the generation of reactive oxygen species (ROS), leading to modulation in antioxidant defenses. Pollutant exposure can potentiate ROS generation during hypoxic events and impair antioxidant defenses, increasing the susceptibility of hypoxia-tolerant fishes, such as the Nile tilapia (Oreochromis niloticus), to oxidative stress. The purpose of this study was to evaluate oxidative stress responses of O. niloticus to acute (3 and 8 h) moderate hypoxia (dissolved oxygen ≤2 mg/L−1) and how these responses are affected by simultaneous exposure to the insecticide fipronil (0.1 and 0.5 µg L−1). Hypoxia exposure for 3 h caused an increase in glutathione peroxidase (GPx) activity in the gill and also increased catalase (CAT) and glutathione S-transferase (GST) activities in the liver. After 8 h of hypoxia, glutathione reductase (GR) activity increased. DNA damage (comet assay) in erythrocytes was reduced by hypoxia after 3 and 8 h. Fipronil exposure for 3 h decreased CAT activity in the gill, both under normoxia and hypoxia. After 8h, the combination of fipronil and hypoxia increased GR activity in the gill. In the liver, fipronil exposure under hypoxia for 3 h increased CAT and GR activities; after 8 h, CAT was decreased, and GST increased. GR was also increased by fipronil under normoxia for 8 h. All treatments reduced lipid peroxidation levels in the gills, but in the liver, lipid peroxidation was increased by fipronil after 3 h under normoxia. Moreover, fipronil exposure under hypoxia for 3 and 8h increased DNA damage in erythrocytes, while 8 h of fipronil exposure under normoxia decreased it, suggesting the activation of DNA repair mechanisms. Results show that both fipronil and hypoxia exposure significantly modulate the oxidative stress parameters of O. niloticus and that the combination of these factors produces more pronounced effects.

Perinatal Inflammation Results in Sex-Dependent Cardiac Dysfunction.

An increased incidence of adult-onset heart failure is seen in individuals born preterm or affected by fetal growth restriction. An adverse maternal environment is associated with both preterm birth and poor fetal development, and postnatal oxygen therapy is frequently required to sustain oxygenation of vulnerable tissues due to lung immaturity. Studies using our murine model of maternal inflammation (LPS) and neonatal hyperoxia exposure (O2) observed pathological changes in cardiac structural proteins and functional analysis with sex dependent differences in pathologies at 10 months of age. Using our previous model, the current investigations tested the hypothesis that early-life perturbations in cardiac structural proteins might predict adult cardiac dysfunction in a sex dependent manner. LPS-exposed females had lower αMHC mRNA and protein at P0 and P7 relative to the saline-exposed females, but these changes did not persist. Male mice exposed to LPS/O2 had normal expression of αMHC mRNA and protein compared to saline/room air controls though P56, when they dramatically increased. Correlative changes were observed in left ventricular function with a more severe phenotype in the males indicating sex-based differences in cardiac adaptation. Our findings demonstrate that early changes in contractile proteins temporally correlate with deficits in cardiac contractility, with a more severe phenotype in males. Our data suggest that similar findings in humans may predict risk for disease in growth-restricted infants.

Hyperoxia Exposure Alters Airway Mucociliary Differentiation and Downregulates Mitochondrial Complex I in Patient Sample-derived Neonatal Tracheal Airway Epithelial Cells

Hyperoxia Exposure Alters Airway Mucociliary Differentiation and Downregulates Mitochondrial Complex I in Patient Sample-derived Neonatal Tracheal Airway Epithelial Cells

Clearing the Air on the Efficacy of Hypoxia Recognition Training

INTRODUCTION: Hypoxia recognition training (HRT) is a requirement for many nations’ military aircrew. The aim of HRT is to enhance the ability of aircrew to recognize and recover from an unexpected in-flight hypoxic exposure; however, there is a paucity of research evaluating the efficacy of HRT and whether current training approaches are optimal. Rather, the benefits of HRT are routinely promulgated based on opinions and anecdotes. Here, we raise some of our concerns with HRT practices in order to stimulate further discussion and research. Our aim is to ensure aircrew are provided with effective training to mitigate the risks associated with hypoxia—and other physiological threats—to promote flight safety. Shaw DM, Harrell JW, Gant N, Peacock DS. Clearing the air on the efficacy of hypoxia recognition training. Aerosp Med Hum Perform. 2024; 95(11):871–872.

Hypoxia-Induced Mitochondrial ROS and Function in Pulmonary Arterial Endothelial Cells.

Pulmonary artery endothelial cells (PAECs) are a major contributor to hypoxic pulmonary hypertension (PH) due to the possible roles of reactive oxygen species (ROS). However, the molecular mechanisms and functional roles of ROS in PAECs are not well established. In this study, we first used Amplex UltraRed reagent to assess hydrogen peroxide (H2O2) generation. The result indicated that hypoxic exposure resulted in a significant increase in Amplex UltraRed-derived fluorescence (i.e., H2O2 production) in human PAECs. To complement this result, we employed lucigenin as a probe to detect superoxide (O2-) production. Our assays showed that hypoxia largely increased O2- production. Hypoxia also enhanced H2O2 production in the mitochondria from PAECs. Using the genetically encoded H2O2 sensor HyPer, we further revealed the hypoxic ROS production in PAECs, which was fully blocked by the mitochondrial inhibitor rotenone or myxothiazol. Interestingly, hypoxia caused an increase in the migration of PAECs, determined by scratch wound assay. In contrast, nicotine, a major cigarette or e-cigarette component, had no effect. Moreover, hypoxia and nicotine co-exposure further increased migration. Transfection of lentiviral shRNAs specific for the mitochondrial Rieske iron-sulfur protein (RISP), which knocked down its expression and associated ROS generation, inhibited the hypoxic migration of PAECs. Hypoxia largely increased the proliferation of PAECs, determined using Ki67 staining and direct cell number accounting. Similarly, nicotine caused a large increase in proliferation. Moreover, hypoxia/nicotine co-exposure elicited a further increase in cell proliferation. RISP knockdown inhibited the proliferation of PAECs following hypoxia, nicotine exposure, and hypoxia/nicotine co-exposure. Taken together, our data demonstrate that hypoxia increases RISP-mediated mitochondrial ROS production, migration, and proliferation in human PAECs; nicotine has no effect on migration, increases proliferation, and promotes hypoxic proliferation; the effects of nicotine are largely mediated by RISP-dependent mitochondrial ROS signaling. Conceivably, PAECs may contribute to PH via the RISP-mediated mitochondrial ROS.

Late gestational hypoxia exposure impacts lung and pulmonary vascular outcomes in the neonatal and adult offspring

Late gestational hypoxia exposure impacts lung and pulmonary vascular outcomes in the neonatal and adult offspring

Changes in immune cell populations during acclimatization to high altitude.

The immune response to acute hypoxemia may play a critical role in high-altitude acclimatization and adaptation. However, if not properly controlled, hypoxemia-induced inflammation may exacerbate high-altitude pathologies, such as acute mountain sickness (AMS), or other hypoxia-related clinical conditions. Several studies report changes in immune cell subsets at high altitude. However, the mechanisms underlying these changes, and if these alterations are beneficial or maladaptive, remains unknown. To address this, we performed multiparameter flow cytometry on peripheral blood mononuclear cells (PBMCs) collected throughout 3 days of high-altitude acclimatization in healthy sea-level residents (n = 20). Additionally, we conducted invitro stimulation assays to test if high-altitude hypoxia exposure influences responses of immune cells to subsequent inflammatory stimuli. We found several immune populations were altered at high altitude, including monocytes, T cells, and B cells. Some changes in immune cell populations are potentially correlated with AMS incidence and severity. Invitro high-altitude PBMC cultures stimulated with lipopolysaccharide (LPS) showed no changes in pro-inflammatory cytokine production after 1 day at high-altitude. However, by day three pro-inflammatory cytokine production in response to LPS decreased significantly. These results indicate that high-altitude exposure may initiate an inflammatory response that encompasses innate immune sensitization, with adaptive immune suppression following acclimatization.

Rewiring of Uric Acid Metabolism in the Intestine Promotes High-Altitude Hypoxia Adaptation in Humans.

Adaptation to high-altitude hypoxia is characterized by systemic and organ-specific metabolic changes. This study investigates whether intestinal metabolic rewiring is a contributing factor to hypoxia adaptation. We conducted a longitudinal analysis over 108 days, with seven time points, examining fecal metabolomic data from a cohort of 46 healthy male adults traveling from Chongqing (a.s.l. 243 m) to Lhasa (a.s.l. 3,658 m) and back. Our findings reveal that short-term hypoxia exposure significantly alters intestinal metabolic pathways, particularly those involving purines, pyrimidines, and amino acids. A notable observation was the significantly reduced level of intestinal uric acid, the end product of purine metabolism, during acclimatization (also called acclimation) and additional two long-term exposed cohorts (Han Chinese and Tibetans) residing in Shigatse, Xizang (a.s.l. 4,700 m), suggesting that low intestinal uric acid levels facilitate adaptation to high-altitude hypoxia. Integrative analyses with gut metagenomic data showed consistent trends in intestinal uric acid levels and the abundance of key uric acid-degrading bacteria, predominantly from the Lachnospiraceae family. The sustained high abundance of these bacteria in the long-term resident cohorts underscores their essential role in maintaining low intestinal uric acid levels. Collectively, these findings suggest that the rewiring of intestinal uric acid metabolism, potentially orchestrated by gut bacteria, is crucial for enhancing human resilience and adaptability in extreme environments.

DDIT4 promotes erythroid differentiation and coordinates with SIPA1 to regulate erythroid proliferation in bone marrow of high altitude erythrocytosis

Erythrocytosis moderately enhances the oxygen-carrying capacity of the blood and is considered a characteristic response of individuals adapting from low-altitude regions to high-altitude regions. Nevertheless, erythrocytosis can also turn excessive and result in maladaptive syndromes, such as high altitude polycythemia (HAPC). The increased differentiation or proliferation of erythroid cells in the bone marrow may be a crucial factor leading to accumulation of peripheral erythroid cells. However, the mechanism of erythroid regulation within the bone marrow of high-altitude erythrocytosis remains insufficiently systematically observed. We utilized single-cell transcription sequencing to characterize bone marrow cells following chronic hypoxic exposure and found that bone marrow erythrocytosis is associated with the accumulation of Baso-E, Poly-E, and Ortho-E cells at the terminal stage of erythroid lineage differentiation. Through analysis of differential gene expression and localization in differentiated cells within the erythroid lineage, we confirmed that DDIT4 expression was localized in advanced differentiated erythroblast including Baso-E, Poly-E and Ortho-E, its expression was significantly enhanced by hypoxia exposure. We demonstrated that overexpression of DDIT4 could promote K562 cell differentiation, and through the IP pull-down interaction protein profile, we found that DDIT4 might participate in regulating the cell cycle by interacting with SIPA1 to promote the proliferation of erythroid cells and may be involved in HAPC.

Chest compression quality decreases in hypoxic conditions simulating an airliner cabin at cruising altitude: a randomized, controlled, double-blind Manikin Study

AbstractAir traveler numbers are predicted to reach 4.0 billion in 2024. Between 1/15,000–50,000 passengers will experience acute medical problems inflight with cardiac arrests requiring cardiopulmonary resuscitation (CPR) accounting for 0.3% of medical emergencies. Hypoxia in airplane cabins could impair oxygenation and physical performance of caregivers. We conducted a randomized controlled, double-blind study to test the hypothesis that hypoxia decreases the effectiveness in performing CPR. We randomized 24 healthcare professionals to two different study arms, each consisting of two conditions: arm (1) ‘hypoxia (FiO2 15%, equivalent to 2400 m altitude)’ versus ‘normoxia’; arm (2) ‘hypoxia + supplemental oxygen’ versus ‘normoxia + supplemental oxygen’. The order of conditions was counterbalanced and a minimum wash-out period of 24 h was granted between conditions. In each condition participants performed a 5-min cardiac compression only CPR (CCO-CPR) using a full-body manikin after one, three and six hours in an altitude chamber. Mixed ANOVAs with post-hoc false-discovery-rate adjusted pairwise comparisons indicated that although compression frequency was maintained, the number of compressions with correct depth was decreased at all times during hypoxia compared to normoxia (all p &lt; 0.002). After 6 h hypoxia exposure, mean compression depth was below the recommended compression depth defined by ERC/AHA guidelines and reduced compared to normoxia (42.4 ± 12.6 mm vs. 54.6 ± 4.3 mm, p &lt; 0.0001). Supplemental oxygen during CCO-CPR in hypoxia prevented the decrease of compression-depth (55.3 ± 3 mm). Extended hypoxia exposure akin to conditions in airplane cabins can reduce quality of chest compressions during CPR. Supplemental oxygen for healthcare providers is an effective countermeasure.

Impact of neonatal hyperoxia on the development of the coronary vascular bed: an experimental model for the study of cardiomyopathy associated with premature birth

Abstract Introduction Very preterm birth (PT; &amp;lt;32 weeks of gestation), nearly 2% of all births, leads to short-term complications such as bronchopulmonary dysplasia and retinopathy of prematurity that are driven by compromised organ vascular development. Adults born preterm display an increased risk of ischaemic cardiomyopathy and heart failure. Our group has shown that neonatal rats exposed to hyperoxia, simulating the PT neonatal conditions, develop cardiomyocytes hypertrophy, fibrosis and cardiac dysfunction, or Oxygen-Induced Cardiomyopathy (OIC). Whether cardiac changes also associate with alterations in vascular development in the left ventricle (LV) remains unknown. Purpose We hypothesized that neonatal exposure to hyperoxia impact the development of the LV vascular network. Methods Male pups were exposed to 80% O2 (OIC) or room air (CTRL) from day 3 (P3) to P10 of life. Hearts were collected at P10, 4- and 16 weeks. Arteriolar length and capillary density per cardiomyocyte were measured using stereology (elastin) and immunofluorescence (WGA, α-SMA, CD31). High-resolution 3D reconstruction of the vascular network was achieved by combining fluorescent labelling of coronaries (anti-α-SMA) and capillaries (anti-CD31) with a tissue-cleaning protocol (iDisco+), allowing detailed morphometric characterization of the vascular network. The expression of vascular endothelial growth factors and receptors (VEGFA, VEGFB, VEGFR 1 and 2, NRP1, and PIGF) were quantified by RT-qPCR and Western blots. Differences between groups were analyzed with Student's t-test (P &amp;lt; 0.05) (N = 6 per group). Results At P10, we observed a notable rise in the number of capillaries per cardiomyocyte (0.88 ± 0.05 vs. 0.62 ± 0.02 mm2) and a significant increase in VEGFA (+76%) and NRP1 (+38%) expression in the LV from OIC vs. CTRL rats. By 4 weeks, the OIC group showed a significant reduction in arteriolar length vs. CTRL (6.51 ± 0.76 vs. 9.77 ± 1.12 m/cm3), coupled with an increase in the number of capillaries per cardiomyocyte (1.11 ± 0.05 vs. 0.85 ± 0.03 mm2). VEGFA was decreased (-14%) and PLGF increased (+24%) in the LV of OIC rats. At 16 weeks, the OIC condition displayed a significant increase in the number of capillaries per cardiomyocyte (1.37 ± 0.03 vs. 0.98 ± 0.07 mm2) and a decrease in VEGFA (-23%), along with reduction in its receptors VEGFR1 (-27%), VEGFR2 (-20%) and NRP1 (-17%). Conclusion OIC resulting from neonatal hyperoxia exposure associates with vascular changes in the LV that persist to adulthood. These changes are characterized by a reduction in arteriolar length and an increase in the number of capillaries, accompanied by modulation of the expression of pro-angiogenic VEGFA and receptors. The impact of these vascular alterations on the susceptibility of the LV to ischemic or hypertension-related damage is to be explored. These findings suggest a crucial mechanistic pathway for understanding the risk of cardiac pathologies associated with preterm birth.

Activation of ALDH2 alleviates hypoxic pulmonary hypertension in mice by upregulating the SIRT1/PGC-1α signaling pathway

To investigate whether activation of mitochondrial acetal dehydrogenase 2 (ALDH2) alleviates hypoxic pulmonary hypertension by regulating the SIRT1/PGC-1α signaling pathway. Thirty 8-week-old C57 BL/6 mice were randomized into control, hypoxia, and hypoxia +Alda-1 (an ALDH2 activator) group (n=10), and the mice in the latter two groups, along with 10 ALDH2 knockout (ALDH2-/-) mice, were exposed to hypoxia (10% O2, 90% N2) with or without daily intraperitoneal injection of Alda-1 for 4 weeks. The changes in right ventricular function and pressure (RVSP) of the mice were evaluated by echocardiography and right ventricular catheter test, and pulmonary artery pressure was estimated based on RVSP. Pulmonary vascular remodeling, right ventricular injury, myocardial α -SMA expression, distal pulmonary arteriole muscle normalization, right ventricular cross-sectional area, myocardial cell hypertrophy, and right cardiac hypertrophy index were assessed with HE staining, immunofluorescence staining and WGA staining, and the expressions of ALDH2, SIRT1, PGC-1α, P16INK4A and P21CIP1 were detected. In pulmonary artery smooth muscle cells with hypoxic exposure, the effect of Alda-1 and EX527 on cell senescence and protein expressions was evaluated using β-galactose staining and Western blotting. The wild-type mice with hypoxic exposure showed significantly increased RVSP, right ventricular free wall thickness and myocardial expressions of P16INK4A and P21CIP1, which were effectively lowered by treatment with Alda-1 but further increased in ALDH2-/- mice. In cultured pulmonary artery smooth muscle cells, hypoxic exposure significantly increased senescent cell percentage and cellular expressions of P16INK4A and P21CIP1, which were all lowered by treatment with Alda-1, but its effect was obviously attenuated by EX527 treatment. ALDH2 alleviates hypoxiainduced senescence of pulmonary artery smooth muscle cells by upregulating the SIRT1/PGC-1α signaling pathway to alleviate pulmonary hypertension in mice.

Hyperbaric oxygen rapidly produces intracellular bioenergetics dysfunction in human pulmonary cells

Hyperoxic exposure lasting days alters mitochondrial bioenergetic and dynamic functions in pulmonary cells as indices of oxygen toxicity. The aim of this study was to examine effects of short duration hyperbaric and hyperoxic exposures to induce oxygen toxicity similarly. Cultured human lung microvascular endothelial cells, human pulmonary artery endothelial cells and A549 cells were exposed to hyperoxia (∼5 % CO2 equivalent, balance O2) under hyperbaric conditions (4.8 ATA) for 1 and 4 h. Measures of mitochondrial dynamics, inner membrane potential, mitochondrial respiration, the intracellular distribution of bioenergetic capacity and respiration complex protein levels were then quantified. Exposures resulted in altered mitochondrial motility, presence of inhomogeneities in respiration parameters, loss of inner membrane potential, and changes in intracellular partitioning of ATP-linked respiration. Changes in the levels of respiration complex protein levels were also found. The combination of hyperoxic exposure with hyperbaric conditions rapidly produced changes in mitochondrial dynamics and bioenergetics in pulmonary cells. These changes are consistent with the onset of pulmonary oxygen toxicity previously known to result from long duration exposure to hyperoxia alone. These findings suggest health caution is warranted in environmental settings in which both hyperoxic and hyperbaric conditions are present. The synergism of hyperoxia and hyperbaria for rapid induction of oxygen toxicity in cellular models has utility for the study of mechanistic determinants of oxygen toxicity, testing of putative therapeutics, and associated investigations of mitochondrial dysfunction.

Copper supplementation alleviates hypoxia‑induced ferroptosis and oxidative stress in neuronal cells.

Hypoxic ischemia is the primary cause of brain damage in newborns. Notably, copper supplementation has potential benefits in ischemic brain damage; however, the precise mechanisms underlying this protective effect remain unclear. In the present study, a hypoxic HT22 cell model was developed to examine the mechanism by which copper mitigates hypoxia‑induced oxidative stress. Cell viability was assessed using the Cell Counting Kit‑8 assay, mitochondrial structure was examined with a transmission electron microscope, intracellular ferrous ions and lipid reactive oxygen species levels in HT22 cells were measured using FerroOrange and BODIPY 581/591 C11 staining, copper content was determined using graphite furnace atomic absorption spectroscopy, and gene and protein expression were analyzed by reverse transcription‑quantitative PCR and western blotting. The present findings indicated that hypoxic exposure may lead to reduced cell viability, along with the upregulation of various markers associated with ferroptosis. Furthermore, hypoxia elevated the levels of reactive oxygen species, hydrogen peroxide and malondialdehyde, and decreased the activity of superoxide dismutase 1 (SOD1) in HT22 cells. In addition, the intracellular copper concentration exhibited a notable decrease, while supplementation with an appropriate dose of copper effectively shielded neurons from hypoxia‑induced oxidative stress and ferroptosis, and elevated cell viability in hypoxia‑exposed HT22 cells through the copper chaperone for superoxide dismutase/SOD1/glutathione peroxidase 4 axis. In conclusion, the present study identified a novel function of copper in protecting neurons from oxidative stress and ferroptosis under hypoxic conditions, providing fresh insights into the therapeutic potential of copper in mitigating hypoxia‑induced neuronal injury.

Effects of Acute Hypoxic Exposure in Simulated Altitude in Healthy Adults on Cognitive Performance: A Systematic Review and Meta-Analysis.

The neurocognitive response following hypoxia has received special interest. However, it is necessary to understand the impact of acute hypoxic exposure induced by simulated altitude on cognitive performance. This study aimed to determine the effects of acute hypoxic exposure in simulated altitude in healthy adults on reaction time, response accuracy, memory, and attention. Five electronic databases were searched. The inclusion criteria were: (1) Experimental studies involving a hypoxia intervention induced by a hypoxic air generator to determine the effects on cognitive performance; and (2) Conducted in adults (males and/or females; aged 18-50 years) without pathologies or health/mental problems. Four meta-analyses were performed: (1) reaction time, (2) response accuracy, (3) memory, and (4) attention. Finally, 37 studies were included in the meta-analysis. Hypoxia exposure induced detrimental effects on reaction time (standard mean difference (SMD) -0.23; 95% confidence interval (CI) -0.38--0.07; p = 0.004), response accuracy (SMD -0.20; 95% CI -0.38--0.03; p = 0.02), and memory (SMD -0.93; 95% CI: -1.68--0.17; p = 0.02). Nevertheless, attention was not affected during hypoxia exposure (SMD -0.06; 95% CI: -0.23-0.11; p = 0.47). Acute exposure to hypoxia in controlled lab conditions appears to be detrimental to cognitive performance, specifically in reaction time, response accuracy, and memory.

Systemic Inflammatory Effect of Hypobaria During Aeromedical Evacuation after Porcine Traumatic Brain Injury.

Traumatic brain injury (TBI)-related morbidity is caused largely by secondary injury resulting from hypoxia, excessive sympathetic drive, and uncontrolled inflammation. Aeromedical evacuation (AE) is used by the military for transport of wounded soldiers to higher levels of care. We hypothesized that the hypobaric, hypoxic conditions of AE may exacerbate uncontrolled inflammation after TBI that could contribute to more severe TBI-related secondary injury. Thirty-six female pigs were used to test TBI vs Sham TBI, hypoxia vs normoxia, and hypobaria vs ground conditions. TBI was induced by controlled cortical injury, hypobaric conditions of 12,000 ft were established in an altitude chamber, and hypoxic exposure was titrated to 85% SpO 2 while at altitude. Serum cytokines, ubiquitin C-terminal hydrolase L1, and TBI biomarkers were analyzed via ELISA. Gross analysis and staining of cortex and hippocampus tissue was completed for glial fibrillary acidic protein and phosphorylated tau. Serum interleukin-1β, interleukin-6, and tumor necrosis factor-α were significantly elevated after TBI in pigs exposed to altitude-induced hypobaria/hypoxia, as well as hypobaria alone, compared with ground level/normoxia. No difference in TBI biomarkers after TBI or hypobaric, hypoxic exposure was noted. No difference in brain tissue glial fibrillary acidic protein or phosphorylated tau when comparing the most different conditions of Sham TBI + ground or normoxia with the TBI + hypobaria/hypoxia group was noted. The hypobaric environment of AE induces systemic inflammation after TBI. Severe inflammation may play a role in exacerbating secondary injury associated with TBI and contribute to worse neurocognitive outcomes. Measures should be taken to minimize barometric and oxygenation changes during AE after TBI.