Acute Hypoxic Exposure Research Articles

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

BackgroundHigh-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.MethodsC57BL/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.ResultsThe 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.ConclusionsHypoxia 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.E5r9nDKChFa7F_nrUkRwh3Video abstract

A rare clinical case of household gas leak leading to severe asphixia

A rare case of severe asphyxia in a young patient due to household gas leakage WAS presented. The patient was found in an unconscious state with signs of respiratory failure at home, requiring respiratory support at the prehospital stage. The patient had a picture of damage to the circulatory organs with the development of acute myocardial ischemia without damage and reactive hydropericardium, respiratory organs in the form of hypoxic pulmonary edema, complicated by the development of bilateral community-acquired pneumonia, hydrothorax and severe respiratory failure, damage to the nervous system with the development of hypoxic encephalopathy with loss of consciousness and bilateral pyramidal syndrome, digestive organs with the development of reactive posthypoxic hepatopathy. Upon admission to the clinic of the field therapy of the Military Medical Academy of S.M. Kirov, which required hospitalization of the patient in the intensive care unit. It was possible to fully stop severe multiple organ damage that developed as a result of acute hypoxic exposure as a result of the complex treatment. This clinical case clearly demonstrates the importance of emergency, systematic and full-fledged intensive care at all stages of providing care to people with acute hypoxic lesions of organs and systems, including severe community-acquired pneumonia and hypoxic myocardial dystrophy. The influence of the early intensive care initiation and timely evacuation at the stage of qualified and specialized medical care on the effectiveness of therapeutic measures is discussed as this plays a fundamental role in the survival of this category of patients. In general, with timely and full-fledged therapeutic measure implementation aimed at treating complications, even severe acute hypoxic organs lesions and systems are reversible, although this may require long-term inpatient treatment and rehabilitation measures in a military sanatorium-resort organization condition of a therapeutic profile, as well as conducting a military medical examination to establish the fitness category for further military service.

Role of microglia in blood pressure and respiratory responses to acute hypoxic exposure in rats

Microglia modulate cardiorespiratory activities during chronic hypoxia. It has not been clarified whether microglia are involved in the cardiorespiratory responses to acute hypoxia. Here we investigated this issue by comparing cardiorespiratory responses to two levels of acute hypoxia (13% O2 for 4 min and 7% O2 for 5 min) in conscious unrestrained rats before and after systemic injection of minocycline (MINO), an inhibitor of microglia activation. MINO increased blood pressure but not lung ventilation in the control normoxic condition. Acute hypoxia stimulated cardiorespiratory responses in MINO-untreated rats. MINO failed to significantly affect the magnitude of hypoxia-induced blood pressure elevation. In contrast, MINO tended to suppress the ventilatory responses to hypoxia. We conclude that microglia differentially affect cardiorespiratory regulation depending on the level of blood oxygenation. Microglia suppressively contribute to blood pressure regulation in normoxia but help maintain ventilatory augmentation in hypoxia, which underscores the dichotomy of central regulatory pathways for both systems.

Initiating daily acute intermittent hypoxia (dAIH) therapy at 1-week after contusion spinal cord injury (SCI) improves lower urinary tract function in rat

Spinal cord injury (SCI) above the level of the lumbosacral spinal cord produces lower urinary tract (LUT) dysfunction, resulting in impairment of urine storage and elimination (voiding). While spontaneous functional recovery occurs due to remodeling of spinal reflex micturition pathways, it is incomplete, indicating that additional strategies to further augment neural plasticity following SCI are essential. To this end, acute intermittent hypoxia (AIH) exposure has been proposed as a therapeutic strategy for improving recovery of respiratory and other somatic motor function following SCI; however, the impact of AIH as a therapeutic intervention to improve LUT dysfunction remains to be determined. Therefore, we examined the effects of daily AIH (dAIH) on both spontaneous micturition patterns and reflex micturition event (rME) behaviors in adult female Sprague-Dawley rats with mid-thoracic moderate contusion SCI. For these experiments, dAIH gas exposures (five alternating 3 min 12% O2 and 21% O2 episodes) were delivered for 7 consecutive days beginning at 1-week after SCI, with awake micturition patterns being evaluated weekly for 2–3 sessions before and for 4 weeks after SCI and rME behaviors elicited by continuous infusion of saline into the bladder being evaluated under urethane anesthesia at 4-weeks after SCI; daily normoxia (dNx; 21% O2 episodes) served as a control. At 1-week post-SCI, both an areflexic phenotype (i.e., no effective voiding events) and a functional voiding phenotype (i.e., infrequent voiding events with large volumes) were observed in spontaneous micturition patterns (as expected), and subsequent dAIH, but not dNx, treatment led to recovery of spontaneous void frequency pattern to pre-SCI levels; both dAIH- and dNx-treated rats exhibited slightly increased void volumes. At 4-weeks post-SCI, rME behaviors showed increased effectiveness in voiding in dAIH-treated (compared to dNx-treated) rats that included an increase in both bladder contraction pressure (delta BP; P = 0.014) and dynamic voiding efficiency (P = 0.018). Based on the voiding and non-voiding bladder contraction behaviors (VC and NVC, respectively) observed in the BP records, bladder dysfunction severity was classified into mild, moderate, and severe phenotypes, and while rats in both treatment groups included each severity phenotype, the primary phenotype observed in dAIH-treated rats was mild and that in dNx-treated rats was moderate (P = 0.044). Taken together, these findings suggest that 7-day dAIH treatment produces beneficial improvements in LUT function that include recovery of micturition pattern, more efficient voiding, and decreased NVCs, and extend support to the use of dAIH therapy to treat SCI-induced LUT dysfunction.

Acute Hypobaric Hypoxia Exposure Causes Neurobehavioral Impairments in Rats: Role of Brain Catecholamines and Tetrahydrobiopterin Alterations.

Hypoxia is a state in which the body or a specific part of the body is deprived of adequate oxygen supply at the tissue level. Sojourners involved in different activities at high altitudes (> 2500m) face hypobaric hypoxia (HH) due to low oxygen in the atmosphere. HH is an example of generalized hypoxia, where the homeostasis of the entire body of an organism is affected and results in neurochemical changes. It is known that lower O2 levels affect catecholamines (CA), severely impairing cognitive and locomotor behavior. However, there is less evidence on the effect of HH-mediated alteration in brain Tetrahydrobiopterin(BH4) levels and its role in neurobehavioral impairments. Hence, this study aimed to shed light on the effect of acute HH on CA and BH4 levels with its neurobehavioral impact on Wistar rat models. After HH exposure, significant alteration of the CA levels in the discrete brain regions, viz., frontal cortex, hippocampus, midbrain, and cerebellum was observed. HH exposure significantly reduced spontaneous motor activity, motor coordination, and spatial memory. The present study suggests that the HH-induced behavioral changes might be related to the alteration of the expression pattern of CA and BH4-related genes and proteins in different rat brain regions. Overall, this study provides novel insights into the role of BH4 and CA in HH-induced neurobehavioral impairments.

Developmental oxygen preadapts ventricular function of juvenile American alligators, Alligator mississippiensis.

Developmental oxygen is a powerful stressor that can induce morphological and functional changes in the cardiovascular systems of embryonic and juvenile vertebrates. This plasticity has been ascribed, at least in part, to the unique status of the developing cardiovascular system, which undergoes organogenesis while meeting the tissue oxygen demands of the embryo. We have previously reported an array of functional and morphological changes in embryonic American alligators that persist into juvenile life. Most notably, cardiac enlargement as well as functional parameters of anesthetized juvenile alligators remains after embryonic hypoxic exposure. Because the effects of developmental oxygen in crocodilians have only been investigated in anesthetized animals, we explored the pressure dynamics of both ventricles as well as systemic pressure in response to stressors of acute hypoxia and swimming. Our current findings demonstrate that developmental programming of cardiac function (intraventricular pressure and heart rate) does persist into juvenile life, but it is chamber-specific and depends on the experimental manipulation. Acute hypoxic exposure revealed that juvenile alligators that had experienced 10% O2 as embryos maintain right ventricle function and increase left ventricle function during exposure. Finally, the data indicate blood flow in the left aorta must originate from the left ventricle during acute hypoxia and swimming.

Remote ischemic preconditioning enhances aerobic performance by accelerating regional oxygenation and improving cardiac function during acute hypobaric hypoxia exposure.

Remote ischemic preconditioning (RIPC) may improve exercise performance. However, the influence of RIPC on aerobic performance and underlying physiological mechanisms during hypobaric hypoxia (HH) exposure remains relatively uncertain. Here, we systematically evaluated the potential performance benefits and underlying mechanisms of RIPC during HH exposure. Seventy-nine healthy participants were randomly assigned to receive sham intervention or RIPC (4 × 5 min occlusion 180 mm Hg/reperfusion 0 mm Hg, bilaterally on the upper arms) for 8 consecutive days in phases 1 (24 participants) and phase 2 (55 participants). In the phases 1, we measured the change in maximal oxygen uptake capacity (VO2max) and muscle oxygenation (SmO2) on the leg during a graded exercise test. We also measured regional cerebral oxygenation (rSO2) on the forehead. These measures and physiological variables, such as cardiovascular hemodynamic parameters and heart rate variability index, were used to evaluate the intervention effect of RIPC on the changes in bodily functions caused by HH exposure. In the phase 2, plasma protein mass spectrometry was then performed after RIPC intervention, and the results were further evaluated using ELISA tests to assess possible mechanisms. The results suggested that RIPC intervention improved VO2max (11.29%) and accelerated both the maximum (18.13%) and minimum (53%) values of SmO2 and rSO2 (6.88%) compared to sham intervention in hypobaric hypoxia exposure. Cardiovascular hemodynamic parameters (SV, SVRI, PPV% and SpMet%) and the heart rate variability index (Mean RR, Mean HR, RMSSD, pNN50, Lfnu, Hfnu, SD1, SD2/SD1, ApEn, SampEn, DFA1and DFA2) were evaluated. Protein sequence analysis showed 42 unregulated and six downregulated proteins in the plasma of the RIPC group compared to the sham group after HH exposure. Three proteins, thymosin β4 (Tβ4), heat shock protein-70 (HSP70), and heat shock protein-90 (HSP90), were significantly altered in the plasma of the RIPC group before and after HH exposure. Our data demonstrated that in acute HH exposure, RIPC mitigates the decline in VO2max and regional oxygenation, as well as physiological variables, such as cardiovascular hemodynamic parameters and the heart rate variability index, by influencing plasma Tβ4, HSP70, and HSP90. These data suggest that RIPC may be beneficial for acute HH exposure.

Unravelling the characterization of hypoxia‐inducible factor‐1α ( HIF‐1α ) and antioxidant enzymes in clam Cyclina sinensis in response to hypoxia

Aquatic hypoxia has negative or detrimental effects on clams. To cope with hypoxia stress, a complex series of physiological and biochemical strategies can be employed in clams. Hypoxia-inducible factor-1α (HIF-1α) and antioxidant enzymes are commonly found in aquatic animals as an adaptation against hypoxia. In the present study, we cloned the HIF-1α sequence in clam Cyclina sinensis, and it consists of 2654 base pairs (bp) carrying a single open-reading frame that encompasses 2235 bp of the coding region. The predicted C. sinensis HIF-1α protein (744 amino acids) has the conserved HLH-PAS domain, which contained one N-terminal basic helix–loop–helix (bHLH) domain and two Per-ARNT-Sim A/B (PAS) domains, followed by PAS-associated C-terminal (PAC) domain. HIF-1α is expressed predominantly in gills. Exposed to hypoxia, the transcript level of HIF-1α was significantly up-regulated in response to hypoxia, and then, the transcript level declined continuously with the time elapsed. The antioxidant enzymes (SOD, CAT and GSH-PX) in gills were increased initially and then decreased after acute hypoxia exposure. Our study indicates that the HIF-1α gene and antioxidant enzymes may play an important role in cope with acute hypoxia exposure.

Tetraplegia is associated with increased hypoxic ventilatory response during nonrapid eye movement sleep

People with cervical spinal cord injury (SCI) are likely to experience chronic intermittent hypoxia while sleeping. The physiological effects of intermittent hypoxia on the respiratory system during spontaneous sleep in individuals with chronic cervical SCI are unknown. We hypothesized that individuals with cervical SCI would demonstrate higher short‐ and long‐term ventilatory responses to acute intermittent hypoxia (AIH) exposure than individuals with thoracic SCI during sleep. Twenty participants (10 with cervical SCI [9 male] and 10 with thoracic SCI [6 male]) underwent an AIH and sham protocol during sleep. During the AIH protocol, each participant experienced 15 episodes of isocapnic hypoxia using mixed gases of 100% nitrogen (N2) and 40% carbon dioxide (CO2) to achieve an oxygen saturation of less than 90%. This was followed by two breaths of 100% oxygen (O2). Measurements were collected before, during, and 40 min after the AIH protocol to obtain ventilatory data. During the sham protocol, participants breathed room air for the same amount of time that elapsed during the AIH protocol and at approximately the same time of night. Hypoxic ventilatory response (HVR) during the AIH protocol was significantly higher in participants with cervical SCI than those with thoracic SCI. There was no significant difference in minute ventilation (V .E.), tidal volume (V .T.), or respiratory frequency (f) during the recovery period after AIH in cervical SCI compared to thoracic SCI groups. Individuals with cervical SCI demonstrated a significant short‐term increase in HVR compared to thoracic SCI. However, there was no evidence of ventilatory long‐term facilitation following AIH in either group.

How does multi-set high-load resistance exercise impact neuromuscular function in normoxia and hypoxia?

ABSTRACT This study examined whether hypoxia during multi-set, high-load resistance exercise alters neuromuscular responses. Using a single-blinded (participants), randomised crossover design, eight resistance-trained males completed five sets of five repetitions of bench press at 80% of one repetition maximum in moderate normobaric hypoxia (inspiratory oxygen fraction = 0.145) and normoxia. Maximal isometric bench press trials were performed following the warm-up, after 10 min of altitude priming and 5 min post-session (outside, inside and outside the chamber, respectively). Force during pre-/post-session maximal voluntary isometric contractions and bar velocity during exercise sets were measured along with surface electromyographic (EMG) activity of the pectoralis major, anterior deltoid and lateral and medial triceps muscles. Two-way repeated measures ANOVA (condition×time) were used. A significant time effect (p = 0.048) was found for mean bar velocity, independent of condition (p = 0.423). During sets of the bench press exercise, surface EMG amplitude of all studied muscles remained unchanged (p > 0.187). During maximal isometric trials, there were no main effects of condition (p > 0.666) or time (p > 0.119), nor were there any significant condition×time interactions for peak or mean forces and surface EMG amplitudes (p > 0.297). Lower end-exercise blood oxygen saturation (90.9 ± 1.8 vs. 98.6 ± 0.6%; p < 0.001) and higher blood lactate concentration (5.8 ± 1.4 vs. 4.4 ± 1.6 mmol/L; p = 0.007) values occurred in hypoxia. Acute delivery of systemic normobaric hypoxia during multi-set, high-load resistance exercise increased metabolic stress. However, only subtle neuromuscular function adjustments occurred with and without hypoxic exposure either during maximal isometric bench press trials before versus after the session or during actual exercise sets. Highlights Performing multi-set, high-load bench press resistance exercise in hypoxia accentuates metabolic stress, as evidenced by lower arterial oxygen saturation and higher blood lactate concentration, compared to normoxia. Acute hypoxic exposure doesn’t alter neuromuscular responses during the execution of the sets since mean bar velocity dropped similarly in both conditions from set 2 to set 5 with no difference in peak velocity and surface EMG amplitude of the prime movers during the bench press. Only subtle adjustments in peak or mean force and accompanying surface EMG activity occur with and without hypoxic exposure during maximal isometric bench press trials after a 10-min hypoxic priming period and 5 min after the session in reference to post-warm-up.

Post‐fatigue ability to activate muscle is compromised across a wide range of torques during acute hypoxic exposure

The purpose of this study was to assess how severe acute hypoxia alters the neural mechanisms of muscle activation across a wide range of torque output in a fatigued muscle. Torque and electromyography responses to transcranial and motor nerve stimulation were collected from 10 participants (27 years ± 5 years, 1 female) following repeated performance of a sustained maximal voluntary contraction that reduced torque to 60% of the pre‐fatigue peak torque. Contractions were performed after 2 h of hypoxic exposure and during a sham intervention. For hypoxia, peripheral blood oxygen saturation was titrated to 80% over a 15‐min period and remained at 80% for 2 h. Maximal voluntary torque, electromyography root mean square, voluntary activation and corticospinal excitability (motor evoked potential area) and inhibition (silent period duration) were then assessed at 100%, 90%, 80%, 70%, 50% and 25% of the target force corresponding to the fatigued maximal voluntary contraction. No hypoxia‐related effects were identified for voluntary activation elicited during motor nerve stimulation. However, during measurements elicited at the level of the motor cortex, voluntary activation was reduced at each torque output considered (P = .002, η p 2 = .829). Hypoxia did not impact the correlative linear relationship between cortical voluntary activation and contraction intensity or the correlative curvilinear relationship between motor nerve voluntary activation and contraction intensity. No other hypoxia‐related effects were identified for other neuromuscular variables. Acute severe hypoxia significantly impairs the ability of the motor cortex to voluntarily activate fatigued muscle across a wide range of torque output.

An Inexpensive Open-Source Chamber for Controlled Hypoxia/Hyperoxia Exposure.

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.

The Effect of Acute Intermittent and Continuous Hypoxia on Plasma Circulating ßOHB Levels Under Different Feeding Statuses in Humans.

Introduction: Acute hypoxia is known to increase circulating nonesterified fatty acid (NEFA) levels. Adipose tissue lipolysis is a major source of NEFA into circulation and insulin suppresses this process when the tissue is insulin sensitive. NEFA can be esterified to triglycerides and/or completely/partially oxidized, the latter leading to ketogenesis in the liver. To our knowledge, the effect of hypoxia on ketogenesis, more specifically ß-hydroxybutyrate (ßOHB) levels, remains unknown in humans. Therefore, the objective of this study was to determine the effect of acute intermittent and continuous hypoxia on circulating ßOHB levels under different feeding status. Methods: Plasma samples from three different randomized crossover studies were assessed for ßOHB concentrations. In the first study, 14 healthy men (23 ± 3.5 years) were exposed to 6 h of normoxia or intermittent hypoxia (IH-Fed) (15 hypoxic events/hour) following an isocaloric meal. In the second study, 10 healthy men (26 ± 5.6 years) were exposed to 6 h of continuous normobaric hypoxia (CH-Fasted) (FiO2 = 0.12) or normoxia in the fasting state. In the third study (CH-Fed), 9 healthy men (24 ± 4.5 years) were exposed to 6 h of normoxia or CH in a constant prandial state. ßOHB, NEFA and insulin levels were measured during all sessions. Results: In the IH-Fed study, ßOHB and NEFA levels tended to be greater over 6 h of IH (condition × time interaction, ßOHB p = 0.108 and NEFA p = 0.062) compared to normoxia. In the CH-Fasted study, ßOHB and NEFA levels increased over time in both experimental conditions, this effect being greater under CH (condition × time interaction, ßOHB p = 0.070; NEFA p = 0.046). In the CH-Fed study, ßOHB levels slightly increased up to 180 min before falling back to initial concentrations by the end of the protocol in both normoxia and CH (main effect of time, p = 0.062), while NEFA were significantly higher under CH (p = 0.006). Conclusion: Acute normobaric hypoxia exposure tends to increase plasma ßOHB concentrations over time in healthy men. The stimulating effect of hypoxia on plasma ßOHB levels is however attenuated during postprandial and prandial states.

Dynamic cerebral blood flow changes with FOXOs stimulation are involved in neuronal damage associated with high-altitude cerebral edema in mice

Acute hypobaric hypoxia (AHH) exposure causes altitude mountain sickness (AMS) and life-threatening high altitude cerebral edema (HACE). Despite decades of research, the role of cerebral blood flow (CBF) changes in the pathophysiology of severe AMS remains unclear. The current study evaluated spatiotemporal responses of CBF associated with HACE in mice during the early stages of ascent to high altitudes. First, mice were exposed to AHH to test their tolerance to increasing altitudes (3000–8000 m). Because of its significant influence on both locomotor activity and rotarod behavior tests in mice, further observations were initiated at an altitude of 6000 m to investigate the specific pathophysiology of AMS. Compared with controls, laser speckle contrast imaging (LSCI) revealed a significant decrease in CBF during the early stage (0.5–24 h) at an altitude of 6000 m that was accompanied by a significant increase in brain water content (BWC). Moreover, observations of brain lipid oxidative damage and oxidative stress during the early stage of AHH exposure revealed DNA and cellular damage in cortical and hippocampal regions. Transcriptome profiling of the hippocampus revealed upregulation of forkhead box transcription factors. Similarly, western blot assays revealed upregulation of FOXO1a, FOXO3a, caspase-3 and Bax, and downregulation of Bcl-2, indicating a temporal influence of AHH on mitochondrial function and neuronal apoptosis. Thus, we found that the pathophysiology of HACE occurred with dynamic CBF changes, which triggered oxidative stress and neuronal damage in the mouse brain after AHH exposure. Our findings provide potential strategies for treatment of AHH in the future.

Sexual Dimorphism of Dexamethasone as a Prophylactic Treatment in Pathologies Associated With Acute Hypobaric Hypoxia Exposure.

Dexamethasone can be taken prophylactically to prevent hypobaric hypoxia-associated disorders of high-altitude. While dexamethasone-mediated protection against high-altitude disorders has been clinically evaluated, detailed sex-based mechanistic insights have not been explored. As part of our India-Leh-Dexamethasone-expedition-2020 (INDEX 2020) programme, we examined the phenotype of control (n = 14) and dexamethasone (n = 13) groups, which were airlifted from Delhi (∼225 m elevation) to Leh, Ladakh (∼3,500 m), India, for 3 days. Dexamethasone 4 mg twice daily significantly attenuated the rise in blood pressure, heart rate, pulmonary pressure, and drop in SaO2 resulting from high-altitude exposure compared to control-treated subjects. Of note, the effect of dexamethasone was substantially greater in women than in men, in whom the drug had relatively little effect. Thus, for the first time, this study shows a sex-biased regulation by dexamethasone of physiologic parameters resulting from the hypoxic environment of high-altitude, which impacts the development of high-altitude pulmonary hypertension and acute mountain sickness. Future studies of cellular contributions toward sex-specific regulation may provide further insights and preventive measures in managing sex-specific, high-altitude–related disorders.

Acute high-altitude hypoxia exposure causes neurological deficits via formaldehyde accumulation.

IntroductionAcute high‐altitude hypoxia exposure causes multiple adverse neurological consequences. However, the exact mechanisms are still unclear, and there is no targeted treatment with few side effects. Excessive cerebral formaldehyde (FA) impairs numerous functions, and can be eliminated by nano‐packed coenzyme Q10 (CoQ10).AimsIn this study, we aimed to investigate whether cerebral FA was accumulated after hypobaric hypoxia exposure, and further explored the preventative effect of CoQ10 through FA elimination.ResultsAccumulated cerebral FA was found in C57BL/6 mice after acute high‐altitude hypoxia exposure, which resulted in FA metabolic disturbance with the elevation of semicarbazide‐sensitive amine oxidase, and declination of aldehyde dehydrogenase‐2. Excessive FA was also found to induce neuronal ferroptosis in vivo. Excitingly, administration with CoQ10 for 3 days before acute hypobaric hypoxia reduced cerebral FA accumulation, alleviated subsequent neuronal ferroptosis, and preserved neurological functions.ConclusionCerebral FA accumulation mediates neurological deficits under acute hypobaric hypoxia, and CoQ10 supplementation may be a promising preventative strategy for visitors and sojourners at plateau.

Effect of Cyclooxygenase Inhibitor on Hypoxia Stimulated Cerebral Blood Flow Using Arterial Spin Labeling Magnetic Resonance

IntroductionThe purpose of this study was twofold: 1) to determine microvascular cerebral blood flow (CBF) during hypoxia and 2) to investigate the effect of Ketorolac, a cyclooxygenase (COX) inhibitor, on hypoxia stimulated CBF. Acute exposure to hypoxic conditions leads to an increase in CBF, which may be regionally specific. Studies investigating the effect of hypoxia on CBF have utilized varying gradations and durations of hypoxia and different measuring techniques (transcranial doppler ultrasound or magnetic resonance imaging (MRI)). COX has been shown to significantly contribute to CBF at rest, however during hypoxia research has shown conflicting data on COX contribution to hypoxic CBF. Utilizing arterial spin labeling (ASL), an MRI technique that provides microvascular global and regional perfusion, during hypoxia stimulated CBF and the role of COX. We hypothesized hypoxia will increase CBF non‐uniformly, and COX inhibition with Ketorolac will reduce hypoxic dilation in some, but not all brain regions.Methods6 healthy young adults subjects (24 ± 3 years, 22.4 ± 0.7 BMI, 4 male) were included in this analysis using an institutional review board (IRB)‐approved protocol. Subjects completed an ASL MRI scans (5.5 min each) under the 3 distinct conditions: normoxia, hypoxia, and hypoxia + ketorolac drug infusion. The first ASL scan occurred while the subject breathed ambient air (baseline). Isocapnic hypoxia was then induced by breathing reduced O2 (9‐13%) to reduce arterial saturation to 80‐85% for steady state hypoxia followed by the first hypoxia ASL scan. While hypoxia was maintained, Ketorolac was infused at a rate of 0.495 mg/kg over 3 minutes (average dose 33.9 ± 2.8 mg), the third ASL scan was then completed (hypoxia+ketorolac). ASL analysis included smoothing grey matter, co‐registering and normalizing raw data, brain masking and region of interest processing. Statistics were determined using a Two‐Way Repeated Measures ANOVA with Tukey’s post‐hoc analysis.ResultsData are mean ± SD. SpO2 (98 ± 1%, 82 ± 2%, 82 ± 1%) and ETCO2 (36 ± 1mmHg, 35 ± 2mmHg, 34 ± 2) at baseline, hypoxia, and hypoxia+ketorolac, respectively. Baseline Global CBF (58 ± 15 ml/100g‐1/min‐1) was not significantly different from hypoxia (61 ± 14 ml/100g‐1/min‐1) (p=0.47). Regionally, CBF between baseline and hypoxia were not different in the right/left temporal, occipital, parietal, or frontal lobes (R/L: p=0.47/p=0.98, p=0.59/p=0.49, p=0.46/p=0.63, and p=0.18/0.19, respectively). Ketorolac did not change global CBF during hypoxia (60 ± 17 ml/100g‐1/min‐1) (p=0.96). Regional CBF during hypoxia and hypoxia+ketorolac was not changed in the right/left temporal, occipital, parietal, or frontal lobes (R/L: p=0.96/0.91, p=0.57/0.88, p=0.86/0.99, and p=0.38/0.35, respectively).DiscussionContrary to our hypothesis CBF did not change globally or regionally with hypoxia stimulation. Furthermore, COX inhibition via Ketorolac did not change CBF during hypoxia in any region. This finding corroborates previous studies in animals and macrovascular flow in humans that COX inhibitor Ketorolac acts differently in the brain compared to Indomethacin, despite similar pharmacology. In conclusion, acute hypoxia exposure with Ketorolac did not alter microvascular CBF.

Cardiac baroreflex sensitivity and heart rate variability are lower in humans with high affinity hemoglobin compared to typical affinity hemoglobin

BackgroundHumans with high O2 affinity hemoglobin (HAH) have a markedly lower partial pressure of O2at which 50% of hemoglobin is saturated (P50) and a leftward shift of the oxy‐hemoglobin dissociation curve. Humans with HAH have attenuated heart rate responses during both acute and chronic hypoxic exposure relative to humans with typical P50. Despite the attenuated heart rate responses to hypoxia, there are typically no blood pressure differences found in humans with HAH relative to humans with typical P50. Due to the blunted heart rate and normal blood pressure responses to hypoxia in humans with HAH, this study aimed to investigate the impact of HAH on cardiac autonomic function during normoxia and hypoxia. We hypothesized that humans with HAH would have lower cardiac baroreflex sensitivity (cBRS) and heart rate variability (HRV) during normoxia and hypoxia relative to individuals with typical P50.MethodsNine humans with a HAH mutation (6 female, Age: 40±12yrs, P50: 16±1 mmHg) and 12 controls with typical affinity hemoglobin (6 female, Age: 40±10yrs, P50: 26±1 mmHg) laid supine for 10‐minutes prior to 20‐minutes of isocapnic hypoxia, titrated to reduce arterial O2 pressure to ~50 mmHg (Avg. FiO2 = 11.9±0.0%). Beat‐to‐beat arterial pressures (arterial catheter) and heart rate (electrocardiogram) were continuously recorded. Data were averaged in five‐minute segments starting with the last five minutes of supine normoxic rest. Spontaneous cBRS was quantified using the sequence method. HRV was measured in time and frequency domains. Standard deviation of the RR interval (SDRR) was calculated as the standard deviation of all RR intervals in a data segment. Low frequency (LF) HRV was calculated using Fast Fourier Transformation and assessed as absolute spectral intensity in the LF band (0.04‐0.15Hz).ResultsArterial oxygen (PaO2) and carbon dioxide (PaCO2) pressures were not different between humans with HAH and controls during normoxia or isocapnic hypoxia [PaO2: (HAH vs. Control): 48±3 vs. 47±2 mmHg, p=0.612; PaCO2: (HAH vs. Control): 40±3 vs. 39±1 mmHg, p=0.328] exposure. cBRS was lower in humans with HAH compared to controls in normoxia and throughout isocapnic hypoxia [normoxia (HAH vs. Control): 7±4 vs. 16±10 ms/mmHg; hypoxia minutes 15‐20 (HAH vs. Control): 4±3 vs. 14±11 ms/mmHg; Hb type, p=0.024]. Several metrics of HRV were lower in humans with HAH relative to control (SDRR: Hb type, p≤0.001; LF: Hb type, p=0.030) and HRV was blunted to a similar extent in both groups with hypoxia (SDRR: time effect, p=0.009).ConclusionThe findings of this study are twofold. Compared to controls, humans with HAH have: 1) attenuated cardiac baroreflex sensitivity and 2) lower heart rate variability in both normoxia and isocapnic hypoxia.

Effects of Prolonged Exposure to Hypobaric Hypoxia on Oxidative Stress: Overwintering in Antarctic Concordia Station.

Concordia Station is the permanent, research station on the Antarctic Plateau at 3230 m. During the eleventh winter-over campaign (DC11-2015; February 2015 to November 2015) at Antarctic Concordia Station, 13 healthy team members were studied and blood samples were collected at six different time points: baseline measurements (T0), performed at sea level before the departure, and during the campaign at 3, 7, 20, 90, and 300 days after arrival at Concordia Station. Reducing the partial pressure of O2 as barometric pressure falls, hypobaric hypoxia (HH) triggers several physiological adaptations. Among the others, increased oxidative stress and enhanced generation of reactive oxygen/nitrogen species (ROS/RNS), resulting in severe oxidative damage, were observed, which can share potential physiopathological mechanisms associated with many diseases. This study characterized the extent and time-course changes after acute and chronic HH exposure, elucidating possible fundamental mechanisms of adaptation. ROS, oxidative stress biomarkers, nitric oxide, and proinflammatory cytokines significantly increased (range 24-135%) during acute and chronic hypoxia exposure (peak 20th day) with a decrease in antioxidant capacity (peak 90th day: -52%). Results suggest that the adaptive response of oxidative stress balance to HH requires a relatively long time, more than 300th days, as all the observed variables do not return to the preexposition level. These findings may also be relevant to patients in whom oxygen availability is limited through disease (i.e., chronic heart and lung and/or kidney disease) and/or during long-duration space missions.

Effects of Acute Hypobaric Hypoxia Exposure on Cardiovascular Function in Unacclimatized Healthy Subjects: A "Rapid Ascent" Hypobaric Chamber Study.

Background: This study aimed to observe the effects of a fast acute ascent to simulated high altitudes on cardiovascular function both in the main arteries and in peripheral circulation. Methods: We examined 17 healthy volunteers, between 18 and 50 years old, at sea level, at 3842 m of hypobaric hypoxia and after return to sea level. Cardiac output (CO) was measured with Doppler transthoracic echocardiography. Oxygen delivery was estimated as the product of CO and peripheral oxygen saturation (SpO2). The brachial artery’s flow-mediated dilation (FMD) was measured with the ultrasound method. Post-occlusion reactive hyperemia (PORH) was assessed by digital plethysmography. Results: During altitude stay, peripheral oxygen saturation decreased (84.9 ± 4.2% of pre-ascent values; p < 0.001). None of the volunteers presented any hypoxia-related symptoms. Nevertheless, an increase in cardiac output (143.2 ± 36.2% of pre-ascent values, p < 0.001) and oxygen delivery index (120.6 ± 28.4% of pre-ascent values; p > 0.05) was observed. FMD decreased (97.3 ± 4.5% of pre-ascent values; p < 0.05) and PORH did not change throughout the whole experiment. Τhe observed changes disappeared after return to sea level, and normoxia re-ensued. Conclusions: Acute exposure to hypobaric hypoxia resulted in decreased oxygen saturation and increased compensatory heart rate, cardiac output and oxygen delivery. Pre-occlusion vascular diameters increase probably due to the reduction in systemic vascular resistance preventing flow-mediated dilation from increasing. Mean Arterial Pressure possibly decrease for the same reason without altering post-occlusive reactive hyperemia throughout the whole experiment, which shows that compensation mechanisms that increase oxygen delivery are effective.