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High-altitude pulmonary edema (HAPE) is a fatal threat for sojourners who ascend rapidly without sufficient acclimatization. Acclimatized sojourners and adapted natives are both insensitive to HAPE but have different physiological traits and molecular bases. In this study, based on GSE52209, the gene expression profiles of HAPE patients were compared with those of acclimatized sojourners and adapted natives, with the common and divergent differentially expressed genes (DEGs) and their hub genes identified, respectively. Bioinformatic methodologies for functional enrichment analysis, immune infiltration, diagnostic model construction, competing endogenous RNA (ceRNA) analysis and drug prediction were performed to detect potential biological functions and molecular mechanisms. Next, an array of in vivo experiments in a HAPE rat model and in vitro experiments in HUVECs were conducted to verify the results of the bioinformatic analysis. The enriched pathways of DEGs and immune landscapes for HAPE were significantly different between sojourners and natives, and the common DEGs were enriched mainly in the pathways of development and immunity. Nomograms revealed that the upregulation of TNF-α and downregulation of RPLP0 exhibited high diagnostic efficiency for HAPE in both sojourners and natives, which was further validated in the HAPE rat model. The addition of TNF-α and RPLP0 knockdown activated apoptosis signaling in endothelial cells (ECs) and enhanced endothelial permeability. In conclusion, TNF-α and RPLP0 are shared biomarkers and molecular bases for HAPE susceptibility during the acclimatization/adaptation/maladaptation processes in sojourners and natives, inspiring new ideas for predicting and treating HAPE., (© 2024. The Author(s).)

High-altitude environments present extreme conditions characterized by low barometric pressure and oxygen deficiency, which can disrupt brain functioning and cause edema formation. The objective of the present study is to investigate several biomolecule expressions and their role in the development of High Altitude Cerebral Edema in a rat model. Specifically, the study focuses on analyzing the changes in total arginase, nitric oxide, and lipid peroxidation (MDA) levels in the brain following acute hypobaric hypoxic exposure (7620 m, SO 2 =8.1 %, for 24 h) along with the histopathological assessment. The histological examination revealed increased TNF-α activity, and an elevated number of mast cells in the brain, mainly in the hippocampus and cerebral cortex. The research findings demonstrated that acute hypobaric hypoxic causes increased levels of apoptotic cells, shrinkage, and swelling of neurons, accompanied by the formation of protein aggregation in the brain parenchyma. Additionally, the level of nitric oxide and MDA was found to have increased (p<0.0001), however, the level of arginase decreased indicating active lipid peroxidation and redox imbalance in the brain. This study provides insights into the pathogenesis of HACE by evaluating some biomolecules that play a pivotal role in the inflammatory response and the redox landscape in the brain. The findings could have significant implications for understanding the neuronal dysfunction and the pathological mechanisms underlying HACE development., Competing Interests: Declaration of Competing Interest The authors declared no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: High altitude retinopathy (HAR) is a retinal functional disorder caused by inadequate adaptation after exposure to high altitude. However, the cellular and molecular mechanisms underlying retinal dysfunction remain elusive. Retinal ganglion cell (RGC) injury is the most important pathological basis for most retinal and optic nerve diseases. Studies focusing on RGC injury after high-altitude exposure (HAE) are scanty. Therefore, the present study sought to explore both functional and morphological alterations of RGCs after HAE., Methods: A mouse model of acute hypobaric hypoxia was established by mimicking the conditions of a high altitude of 5000 m. After HAE for 2, 4, 6, 10, 24, and 72 hours, the functional and morphological alterations of RGCs were assessed using retinal hematoxylin and eosin (H&E) sections, retinal whole mounts, transmission electron microscopy (TEM), and the photopic negative response (PhNR) of the electroretinogram., Results: Compared with the control group, the thickness of the ganglion cell layer and retinal nerve fiber layer increased significantly, RGC loss remained significant, and the amplitudes of a-wave, b-wave, and PhNR were significantly reduced after HAE. In addition, RGCs and their axons exhibited an abnormal ultrastructure after HAE, including nuclear membrane abnormalities, uneven distribution of chromatin in the nucleus, decreased cytoplasmic electron density, widening and vacuolization of the gap between axons, loosening and disorder of myelin sheath structure, widening of the gap between myelin sheath and axon membrane, decreased axoplasmic density, unclear microtubule and nerve fiber structure, and abnormal mitochondrial structure (mostly swollen, with widened membrane gaps and reduced cristae and vacuolization)., Conclusions: The study findings confirm that the morphology and function of RGCs are damaged after HAE. These findings lay the foundation for further study of the specific molecular mechanisms of HAR and promote the effective prevention.

Background: High-altitude cerebral edema (HACE) is considered an end-stage acute mountain sickness (AMS) that typically occurs in people after rapid ascent to 2500 m or more. While hypoxia is a fundamental feature of the pathophysiological mechanism of HACE, emerging evidence suggests that inflammation serves as a key risk factor in the occurrence and development of this disease. However, little is known about the molecular mechanism underlying their crosstalk., Methods: A mouse HACE model was established by combination treatment with hypobaric hypoxia exposure and lipopolysaccharides (LPS) stimulation. Lactylated-proteomic analysis of microglia was performed to reveal the global profile of protein lactylation. Molecular modeling was applied to evaluate the 3-D modeling structures. A combination of experimental approaches, including western blotting, quantitative real-time reverse transcriptionpolymerase chain reaction (qRT-PCR), and enzyme-linked immunosorbent assay (ELISA), confocal microscopy and RNA interference, were used to explore the underlying molecular mechanisms., Results: We found that hypoxia exposure increased the lactate concentration and lactylation in mouse HACE model. Moreover, hypoxia aggravated the microglial neuroinflammatory response in a lactate-dependent manner. Global profiling of protein lactylation has shown that a large quantity of lysine-lactylated proteins are induced by hypoxia and preferentially occur in protein complexes, such as the NuRD complex, ribosome biogenesis complex, spliceosome complex, and DNA replication complex. The molecular modeling data indicated that lactylation could affect the 3-D theoretical structure and increase the solvent accessible surface area of HDAC1, MTA1 and Gatad2b, the core members of the NuRD complex. Further analysis by knockdown or selectively inhibition indicated that the NuRD complex is involved in hypoxia-mediated aggravation of inflammation., Conclusions: These results revealed a comprehensive profile of protein lactylation in microglia and suggested that protein lysine lactylation plays an important role in the regulation of protein function and subsequently contributes to the neuroinflammatory response under hypoxic conditions., (© 2024. The Author(s).)

Objective: To establish an animal model of high-altitude cerebral edema (HACE), to explore the altitude and oxygen partial pressure conditions that can lead to obvious clinical manifestations of HACE, and to lay the foundation for further research of the pathogenic mechanisms and intervention strategies of HACE., Methods: Male BALB/c mice of 8 weeks old were randomly assigned to Control and HACE groups. The Control group ( n =10) was treated with normobaric and normoxic conditions, while the HACE groups were placed in hypobaric hypoxic (HH) chambers for the durations of 6 h, 12 h, 24 h, 48 h and 72 h, respectively, receiving treatments of simulated HH conditions at the altitudes of 4000 m ( n =10 for each group receiving different durations of HH treatment), 5000 m ( n =10 for each group receiving different durations of HH treatment), and 6000 m ( n =10 for each group receiving different durations of HH treatment). HE staining was performed to observe the morphological changes of the brain tissue and the appropriate simulated altitude conditions were selected accordingly for the construction and evaluation of the best HACE model. The HACE model was evaluated in the following ways, the mouse brain was weighed and the cerebral edema was measured accordingly, Evans blue (EB) was injected to determine the permeability of the blood-brain barrier (BBB), and the cell apoptosis was determined by immunofluorescence staining., Results: There were no deaths in the groups treated with the HH conditions of the altitudes of 4000 m and 5000 m, while the mortality in the 6000 m altitude treatment groups was 12.2%. HE staining showed no significant changes in brain morphology or structure in the group receiving HH treatment for the altitude of 4000 m. A small amount of brain cell edema was observed in the groups receiving 48 h and 72 h of HH treatment for the altitude of 5000 m. The groups receiving HH treatment for the altitude of 6000 m demonstrated the most prominent modeling effect. HE staining showed increased volume and swelling of brain cells in all the 6000 m groups, especially in the 24 h, 48 h and 72 h treatment groups. In all the 6000 m groups, cell arrangement disorder, gap enlargement, and nuclear contraction were observed. Evaluation of the modeling effect demonstrated that, in the HACE mice model constructed with the HH conditions for the altitude of 6000 m, cerebral edema and EB permeability increased after 12 h HH treatment and there was no obvious apoptosis in the modeling groups receiving different durations of treatment., Conclusion: The HACE model can be established effectively by simulating conditions at the altitude of 6000 m (the atmospheric pressure being 47.19 kPa and the oxygen partial pressure being 9.73 kPa) with a HH chamber., Competing Interests: 利益冲突　所有作者均声明不存在利益冲突, (© 2023《四川大学学报（医学版）》编辑部 版权所有Copyright ©2023 Editorial Board of Journal of Sichuan University (Medical Sciences).)

Background: Trekkers in high altitude of Himalayas could lead to Acute Mountain Sickness and High Altitude Cerebral Edema. This study was conducted to evaluate magnetic resonance imaging findings among the clinically suspected High Altitude Cerebral Edema patients rescued from high altitudes in Nepal Himalayas., Methods: 49 patients with clinically suspected High Altitude Cerebral Edema were retrospectively evaluated in this cross-sectional study who were sent for a brain magnetic resonance imaging. They were categorized in 3 groups according to the magnetic resonance imaging features in this study., Results: There was a slight male preponderance. 6 patients (12.25%) had magnetic resonance imaging findings highly suggestive of High Altitude Cerebral Edema. 5 patients had T2 high signal intensity and restricted diffusion in the splenium of corpus callosum of which 3 had features of microhemorrhage. One patient with normal brain morphology and intensity in T1, T2, and FLAIR images showed innumerable variable-sized microhemorrhages in Susceptibility Weighted Imaging. 14 of patients showed various T2 and FLAIR white matter high signal intensity without restricted diffusion. And one patient had features of subacute lacunar infarcts. 28 patients (57.14 %) showed no abnormal signal changes in the magnetic resonance imaging scan., Conclusions: Typical magnetic resonance imaging features of cytotoxic edema in corpus callosum and microhemorrhage in the patients with High Altitude Cerebral Edema further support the findings in other similar studies. T2 white matter hyperintensities in deep, subcortical or periventricular location and lacunar infarcts could be seen in High Altitude Cerebral Edema. Normal magnetic resonance imaging of the brain is not infrequent.

Background and Purpose: Animal studies suggest that exposure to severe ambient hypoxia for several days may have beneficial long-term effects on neurodegenerative diseases. Because, the acute risks of exposing human beings to prolonged severe hypoxia on brain structure and function are uncertain, we conducted a pilot study in healthy persons., Methods: We included two professional mountaineers (participants A and B) in a 35-day study comprising an acclimatization period and 14 consecutive days with oxygen concentrations between 8% and 8.8%. They underwent cerebral magnetic resonance imaging at seven time points and a cognitive test battery covering a spectrum of cognitive domains at 27 time points. We analysed blood neuron specific enolase and neurofilament light chain levels before, during, and after hypoxia., Results: In hypoxia, white matter volumes increased (maximum: A, 4.3% ± 0.9%; B, 4.5% ± 1.9%) whilst gray matter volumes (A, -1.5% ± 0.8%; B, -2.5% ± 0.9%) and cerebrospinal fluid volumes (A, -2.7% ± 2.4%; B, -5.9% ± 8.2%) decreased. Furthermore, the number (A, 11-17; B, 26-126) and volumes (A, 140%; B, 285%) of white matter hyperintensities increased in hypoxia but had returned to baseline after a 3.5-month recovery phase. Diffusion weighted imaging of the white matter indicated cytotoxic edema formation. We did not observe changes in cognitive performance or biochemical brain injury markers., Discussion: In highly selected healthy individuals, severe sustained normobaric hypoxia over 2 weeks elicited reversible changes in brain morphology without clinically relevant changes in cognitive function or brain injury markers. The finding may pave the way for future translational studies assessing the therapeutic potential of hypoxia in neurodegenerative diseases., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Exposure to hypobaric hypoxia at high altitude puts mountaineers at risk of acute mountain sickness. The carbonic anhydrase inhibitor acetazolamide is used to accelerate acclimatization, when it is not feasible to make a controlled and slow ascend. Studies in rodents have suggested that exposure to hypobaric hypoxia deteriorates bone integrity and reduces bone strength. The study investigated the effect of treatment with acetazolamide and the bisphosphonate, zoledronate, on the skeletal effects of exposure to hypobaric hypoxia. Eighty 16-week-old female RjOrl : SWISS mice were divided into five groups: 1. Baseline; 2. Normobaric; 3. Hypobaric hypoxia; 4. Hypobaric hypoxia + acetazolamide, and 5. Hypobaric hypoxia + zoledronate. Acetazolamide was administered in the drinking water (62 mg/kg/day) for four weeks, and zoledronate (100 μg/kg) was administered as a single subcutaneous injection at study start. Exposure to hypobaric hypoxia significantly increased lung wet weight and decreased femoral cortical thickness. Trabecular bone was spared from the detrimental effects of hypobaric hypoxia, although a trend towards reduced bone volume fraction was found at the L4 vertebral body. Treatment with acetazolamide did not have any negative skeletal effects, but could not mitigate the altitude-induced bone loss. Zoledronate was able to prevent the altitude-induced reduction in cortical thickness. In conclusion, simulated high altitude affected primarily cortical bone, whereas trabecular bone was spared. Only treatment with zoledronate prevented the altitude-induced cortical bone loss. The study provides preclinical support for future studies of zoledronate as a potential pharmacological countermeasure for altitude-related bone loss., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Brent, Simonsen, Thomsen and Brüel.)

The aim of the present study was to investigate the changes in lung histomorphology and oxidative stress, as well as the expression of interleukin (IL)‑17C and other inflammatory factors during acute mountain sickness (AMS) in male Sprague‑Dawley rats and to explore the underlying mechanism. Rats were randomly divided into a control group (0 h) and three hypoxia stress groups, exposed to low‑pressure oxygen storage at a simulated altitude of 6,000 m for 24, 48 and 72 h, respectively. Morphological changes in lung tissue were observed by hematoxylin and eosin staining under light microscopy and transmission electron microscopy. The expression of inflammatory factors IL‑17C, nuclear factor‑κB (NF‑κB), IL‑1β, IL‑6 and tumor necrosis factor‑α (TNF‑α) in lung tissue was assessed by RNA sequencing and verified by reverse transcription‑quantitative PCR (RT‑qPCR) and western blotting (WB). Superoxide dismutase (SOD) and glutathione peroxidase (GSH‑Px) enzyme activity and malondialdehyde (MDA) expression were also measured. Experimental groups were compared to the control group following 24, 48 and 72 h of hypoxic stress. Lung tissue suffered from different degrees of injury, and the damage was the most severe after 48 h of hypoxic stress. RNA sequencing data from the lung tissue of rats from each group suggested that the expression of IL‑17C, NF‑κB, IL‑1β, IL‑6, and TNF‑α increased significantly after hypoxic stress. RT‑qPCR and WB demonstrated that the expression of IL‑17C and NF‑κB increased significantly after hypoxia lasting 48 and 72 h. IL‑1β expression increased significantly after hypoxia stress lasting 24 and 48 h, and the expressions of TNF‑α and IL‑6 increased significantly after hypoxia stress lasting 24, 48 and 72 h (P<0.01). The enzyme activity of SOD and GSH‑Px decreased significantly after lasting 24, 48 and 72 h of hypoxia (P<0.01), and MDA increased significantly after hypoxic stress lasting 48 and 72 h (P<0.01). In conclusion, under hypoxic stress, rats quickly initiate oxidative stress and immune responses. However, with prolonged hypoxic stress time, excessive oxidative stress can further stimulate the immune system in vivo , and release a large quantity of inflammatory factors accumulating in the body. This, in turn, may lead to the occurrence of inflammatory storms and further damage the lung tissue resulting in AMS.

18β-Glycyrrhetinic acid (GA) is the triterpenoid aglycone component of glycyrrhizic acid, a natural product of traditional Chinese medicine, and has been proven to possess a variety of pharmacological effects. The protection function and the mechanism of GA on rats with high-altitude pulmonary hypertension (HAPH) are studied using proton nuclear magnetic resonance ( 1 H NMR) metabonomics technology and biochemical analysis. An HAPH model is established, and 60 male rats are randomly divided into the following groups: Control(normal saline, 0.4 mL/100 g), model (normal saline, 0.4 mL/100 g), Nifedipine (nifedipine, 2.7 mg/kg), and high-, medium-, and low-dose GA groups (100, 50, and 25 mg/kg GA designated as GA.H, GA.M, and GA.L, respectively). Serum biochemical indicators of rats in each group are measured, and pathological changes in the pulmonary artery are observed. 1 H NMR metabonomics technology is used for serum analysis. Results show that GA can significantly reduce pulmonary arterial pressure and malondialdehyde levels and increase the glutathione peroxidase and superoxide dismutase activities in HAPH rats. Pathological results show that GA can alleviate pulmonary artery injuries of HAPH rats. Metabolomics analytical findings show that GA can alleviate the metabolic disorder of HAPH rats through anti-oxidation and anti-inflammatory effects, improve their bodies' ability to resist hypoxia, and restore various metabolic pathways (energy metabolism, amino acid metabolism, and lipid metabolism). GA has potential therapeutic effects on HAPH rats, but its target needs to be further studied., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Following prolonged exposure to hypoxic conditions, for example, due to ascent to high altitude, stroke, or traumatic brain injury, cerebral edema can develop. The exact nature and genesis of hypoxia-induced edema in healthy individuals remain unresolved. We examined the effects of prolonged, normobaric hypoxia, induced by 16 h of exposure to simulated high altitude, on healthy brains using proton, dynamic contrast enhanced, and sodium MRI. This dual approach allowed us to directly measure key factors in the development of hypoxia-induced brain edema: (1) Sodium signals as a surrogate of the distribution of electrolytes within the cerebral tissue and (2) K trans as a marker of blood-brain-barrier integrity. The measurements point toward an accumulation of sodium ions in extra- but not in intracellular space in combination with an intact endothelium. Both findings in combination are indicative of ionic extracellular edema, a subtype of cerebral edema that was only recently specified as an intermittent, yet distinct stage between cytotoxic and vasogenic edemas. In sum, here a combination of imaging techniques demonstrates the development of ionic edemas following prolonged normobaric hypoxia in agreement with cascadic models of edema formation., (© 2021. The Author(s).)

Background: We aimed to review records from 429 patients with high altitude pulmonary edema (HAPE) to identify some of the salient characteristics associated with this condition., Materials and Methods: General information and clinical symptoms, along with laboratory test results from HAPE patients were collected and analyzed. Blood assay results and imaging at admission were compared with those at discharge. Results from routine blood assays were compared among three subgroups of these patients that were generated based upon the duration of their hypoxia exposure., Results: Of these 429 HAPE patients, 9.32% also showed high altitude cerebral edema (HACE). White blood cell and neutrophil counts, as well as levels of alanine aminotransferase and aspartate aminotransferase, uric acid, lactic dehydrogenase and creatine kinase were all increased in HAPE patients, with further increases observed in those with HAPE combined with HACE. Levels of white blood cells, neutrophils, lymphocytes, and hemoglobin concentrations in HAPE patients at admission were significantly higher than that obtained at discharge. White blood cell and neutrophil counts were lower in patients who developed HAPE after a duration of 7 days of high altitude exposure as compared with those who developed the condition within 1 or 3 days., Conclusions: A combination of HAPE and HACE was present in 9.32% of the patients with HAPE. HAPE was more prevalent in males. Hepatocytes and the myocardium were likely sites of damage in patients with HAPE, with more severe damage observed in the patients with HAPE/HACE. White blood cell and neutrophil counts were significantly higher than normal ranges and these levels were negatively correlated with the duration of hypoxia exposure., Competing Interests: Declaration of Competing Interest The author has no financial or other conflicts of interest to disclose., (Copyright © 2021 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

High-altitude pulmonary edema (HAPE) is a life-threatening disease occurs in hypobaric hypoxia (HH) environment, which could be treated by Dexamethasone, but might cause side-effects. Potentilla anserina L polysaccharide (PAP) holds promising physiological and pharmacological properties which could be beneficial for HAPE treatment. In our study, the anti-hypoxia effect of PAP was firstly investigated through anti-normobaric hypoxia test and anti-acute hypoxia test. Then we established a model of HAPE and measured the lung water content, pathological changes and MDA, NO, SOD, GSH concentrations in lung tissues. We also evaluated the protein and mRNA levels of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, VEGF, NF-κB and HIF-1α) by ELISA kits, RT-PCR and Western blotting. As expected, PAP could dramatically reduce the lung water content, alleviate lung tissue injury, and inhibit MDA and NO production, it also promote SOD activity and GSH expression. In addition, it has been found that PAP blocked the NF-κB and HIF-1α signaling pathway activation, inhibited the generation of downstream pro-inflammatory cytokines. Therefore, PAP provides great potential in HAPE treatment mainly through suppression of oxidative stress and inflammatory suppression., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Chinese Yunnan Province, located in the Yunnan-Guizhou Plateau, is a famous tourist paradise where acute high-altitude illness common occurs among lowland people visitors due to non-acclimatization to the acute hypobaric hypoxia (AHH) conditions. Traditional Chinese medicine, such as Qi-Long-Tian (QLT) formula, has shown effectiveness and safety in the treatment of acute high-altitude diseases. The aim of this study was to clarify the therapeutic mechanisms of this traditional formula using a rat model in a simulated plateau environment., Methods: Following testing, lung tissue samples were evaluated by hematoxylin-eosin staining and for biochemical characteristics. mRNA-Seq was used to compare differentially expressed genes in control rats, and in rats exposed to AHH and AHH with QLT treatment., Results: Inflammation-related effectors induced following QLT treatment for AHH included MMP9 and TIMP1, and involved several phosphorylation signaling pathways implicated in AHH pathogenesis such as PI3K/AKT and MAPK signaling., Conclusion: This study provides insights into the major signaling pathways induced by AHH and in the protective mechanisms involved in QLT formula activity.

Background: Acetazolamide is the most common medication used for acute mountain sickness prevention, with speculation that a reduced dose may be as efficacious as standard dosing with fewer side effects., Methods: This double-blind, randomized, controlled noninferiority trial compared acetazolamide 62.5 mg twice daily to the standard dose acetazolamide 125 mg twice daily starting the evening prior to ascent from 1240 m (4100 ft) to 3810 m (12,570 ft) over 4 hours. The primary outcome was acute mountain sickness incidence (ie, headache, Lake Louise Questionnaire ≥3, and another symptom)., Results: A total of 106 participants were analyzed, with 51 (48%) randomized to 125 mg and 55 (52%) to 62.5 mg, with a combined acute mountain sickness incidence of 53 (50%) and mean severity of 3 (± 2.1). The 62.5-mg group failed to fall within the prespecified 26% noninferiority margin for acute mountain sickness incidence (62.5 mg = 30 [55%] vs 125 mg = 23 [45%], 95% confidence interval [CI] -11% to 30%). Participants in the 62.5-mg group had a higher risk of acute mountain sickness (odds ratio = 1.5, 95% CI 0.7-3.2) and moderate acute mountain sickness (odds ratio = 1.8, 95% CI 0.6-5.9), with a number needed to harm (NNH) of 9, with a number needed to treat (NNT) in the 125-mg group of 4.8. Increased acute mountain sickness incidence and symptom severity corresponded to lower weight-based and body mass index dosing, with similar side effects between groups., Conclusion: Acetazolamide 62.5 mg twice daily failed to demonstrate equal effectiveness to 125 mg twice daily for prevention of acute mountain sickness. With increased risk and no demonstrable symptomatic or physiologic benefits, acetazolamide 62.5 mg twice daily should not be recommended for acute mountain sickness prevention., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Excessive erythrocytosis (EE) is a characteristic of chronic mountain sickness (CMS). Currently, the pathogenesis of CMS remains unclear. This study was intended to investigate the role of EPAS1 in the proliferation of erythroblasts in CMS. Changes of HIF-1α and EPAS1/HIF-2α in the bone marrow erythroblasts of 21 patients with CMS and 14 control subjects residing at the same altitudes were determined by RT-qPCR and western blotting. We also developed a lentiviral vector, Lv-EPAS1/sh-EPAS1, to over-express/silence EPAS1 in K562 cells. Cells cycle and proliferation were detected by flow cytometry. Transcriptome analyses were carried out on Illumina. CMS patients showed a higher expression of EPAS1/HIF-2α in the bone marrow erythroblasts than those of controls. Variations in EPAS1 expression in CMS patients were positively correlated with RBC levels, and negatively correlated with SaO 2 . Over-expressing of EPAS1 in K562 cells accelerated the erythroid cells cycle progression and promoted the erythroid cells proliferation-and vice versa. Transcriptome data indicated that proliferation-related DEGs were significantly enriched in EPAS1 overexpression/silencing K562 cells. Our results suggest that EPAS1 might participate in the pathogenesis of EE by regulating the proliferation of erythroblasts., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Brain is well known for its disproportionate oxygen consumption and high energy-budget for optimal functioning. The decrease in oxygen supply to brain, thus, necessitates rapid activation of adaptive pathways - the absence of which manifest into vivid pathological conditions. Amongst these, oxygen sensing in glio-vascular milieu and H 2 S-dependent compensatory increase in cerebral blood flow (CBF) is a major adaptive response. We had recently demonstrated that the levels of H 2 S were significantly decreased during chronic hypobaric hypoxia (HH)-induced neuro-pathological effects. The mechanistic basis of this phenomenon, however, remained to be deciphered. We, here, describe experimental evidence for marked limitation of cysteine during HH - both in animal model as well as human volunteers ascending to high altitude. We show that the preservation of brain cysteine level, employing cysteine pro-drug (N-acetyl- L -cysteine, NAC), markedly curtailed effects of HH - not only on endogenous H 2 S levels but also, impairment of spatial reference memory in our animal model. We, further, present multiple lines of experimental evidence that the limitation of cysteine was causally governed by physiological propensity of brain to utilize cysteine, in cystathionine beta synthase (CBS)-dependent manner, past its endogenous replenishment potential. Notably, decrease in the levels of brain cysteine manifested despite positive effect (up-regulation) of HH on endogenous cysteine maintenance pathways and thus, qualifying cysteine as a conditionally essential nutrient (CEN) during HH. In brief, our data supports an adaptive, physiological role of CBS-mediated cysteine-utilization pathway - activated to increase endogenous levels of H 2 S - for optimal responses of brain to hypobaric hypoxia., Competing Interests: Declaration of competing interest The authors have declared that no conflict of interest exists., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Venous thrombo-embolism (VTE) is multi-factorial disease involving several genetic and acquired risk factors responsible for its onset. It may occur spontaneously upon climbing at High Altitude (HA). Several studies demonstrated that hypoxic conditions prevailing at HA pose an independent risk factor for VTE; however, molecular mechanism remains unknown. Present study aims to identify genes associated with HA-induced VTE pathophysiology using real time TaqMan Low-Density Array (TLDA) of known candidate genes. Gene expression of total 93 genes were studied and analyzed in patients of VTE from HA (HA-VTE) and from sea level (SL-VTE) in comparison to respective controls. Both HA-VTE and SL-VTE patients showed up-regulation of 37 genes involved in blood coagulation cascade, clot formation, platelet formation, endothelial response, angiogenesis, cell adhesion and calcium channel activity. Seven genes including ACE, EREG, C8A, DLG2, USF1, F2 and PCDHA7 were up-regulated in both HA-controls and VTE patients (both HA-VTE and SL-VTE) indicating their role during VTE event and also upon HA exposure. Ten genes; CDH18, FGA, EDNBR, GATA2, MAPK9, BCAR1, FRK, F11, PCDHA1 and ST8SIA4 were uniquely up-regulated in HA-VTE. The differentially expressed genes from the present study could be determining factors for HA-VTE susceptibility and provide insights into VTE occurrence at HA., Competing Interests: Declaration of competing interest The manuscript has been read and approved for submission to ‘Thrombosis Research’ by all authors. No potential conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose of Review: The erythrocyte is the most abundant cell type in our body, acting as both a carrier/deliverer and sensor of oxygen (O2). Erythrocyte O2 delivery capacity is finely regulated by sophisticated metabolic control. In recent years, unbiased and robust human metabolomics screening and mouse genetic studies have advanced erythroid research revealing the differential role of erythrocyte hypoxic metabolic reprogramming in normal individuals at high altitudes and patients facing hypoxia, such as sickle cell disease (SCD) and chronic kidney disease (CKD). Here we summarize recent progress and highlight potential therapeutic possibilities., Recent Findings: Initial studies showed that elevated soluble CD73 (sCD73, converts AMP to adenosine) results in increased circulating adenosine that activates the A2B adenosine receptor (ADORA2B). Signaling through this axis is co-operatively strengthened by erythrocyte-specific synthesis of sphingosine-1-phosphate (S1P). Ultimately, these mechanisms promote the generation of 2,3-bisphosphoglycerate (2,3-BPG), an erythrocyte-specific allosteric modulator that decreases haemoglobin--O2-binding affinity, and thus, induces deoxygenated sickle Hb (deoxyHbS), deoxyHbS polymerization, sickling, chronic inflammation and tissue damage in SCD. Similar to SCD, plasma adenosine and erythrocyte S1P are elevated in humans ascending to high altitude. At high altitude, these two metabolites are beneficial to induce erythrocyte metabolic reprogramming and the synthesis of 2,3-BPG, and thus, increase O2 delivery to counteract hypoxic tissue damage. Follow-up studies showed that erythrocyte equilibrative nucleoside transporter 1 (eENT1) is a key purinergic cellular component controlling plasma adenosine in humans at high altitude and mice under hypoxia and underlies the quicker and higher elevation of plasma adenosine upon re-ascent because of prior hypoxia-induced degradation of eENT1. More recent studies demonstrated the beneficial role of erythrocyte ADORA2B-mediated 2,3-BPG production in CKD., Summary: Taken together, these findings revealed the differential role of erythrocyte hypoxic metabolic reprogramming in normal humans at high altitude and patients with CKD vs. SCD patients and immediately suggest differential and precision therapies to counteract hypoxia among these groups.

In chronic mountain sickness (CMS) patients, the structure of the brain, memory and cognition are often irreversibly damaged by chronic hypoxia due to red blood cell overcompensation, elevated haemoglobin and blood stasis. In this study, we aimed to evaluate this damage using diffusion tensor imaging (DTI) and to study the correlations among the fractional anisotropy (FA),the apparent diffusion coefficient (ADC) value, the severity index of CMS and the simple Mental State Examination (MMSE) score in CMS patients. A total of 17 patients with CMS and 15 healthy controls were recruited for conventional brain magnetic resonance imaging (MRI) and DTI scans, and ADC images were reconstructed along with FA and FA colour maps. The FA and ADC values of the selected regions of interest (ROIs) were measured and compared. The FA and ADC values were also compared with the haemoglobin (Hb) and MMSE scores. CMS patients are prone to intracranial ischaemia, infarction and haemorrhage. Multiple structural changes occur in the brain of CMS patients, and these changes are related to the severity of the disease and cognitive function variation. The white matter fibre bundles of CMS patients showed no obvious damage, except in the ischaemic site.

Background: In human beings exposed to high altitude, cerebral magnetic resonance imaging (cMRI) revealed alterations ranging from subclinical cerebral edema formation to subtle brain abnormalities. Yet, brain structure after adaptation to high altitude and their recovery after return to lowlands have been rarely investigated. We, therefore, examined 10 healthy individuals by cMRI before, 12 hours after descent (R + 12h), and again 3.5 months (R + 3.5m) after a 7-day high altitude exposure at 4554 m. Results: After their 3-day lasting, stepwise ascent to 4554 m, all subjects suffered acute mountain sickness with a mean Lake Louise score of 5.8 ± 1.7 after the first night at that altitude. Acute mountain sickness completely resolved after 4 days at 4554 m. While 12 hours after descent mean white and gray matter volumes were increased compared with before altitude exposure ( p  = 0.045 and p  = 0.002), these volumes were normalized on R + 3.5m. Moreover, we observed significant focal volume alterations likely attributed to either vasogenic or cytotoxic edema formation. Two subjects presented new brain findings after altitude exposure. In one individual the number of preexisting white matter hyperintensities (WMHI) transiently increased, in the other individual a reversible splenial lesion syndrome (RESLES) emerged. Both findings had resolved 15 and 8 days after descent, respectively. None developed structural lesions like brain atrophy, cerebral infarcts, microbleeds, or high-altitude cerebral edema. Discussion: Three days after complete recovery from acute mountain sickness and after return to low altitude, subclinical vasogenic and cytotoxic edema, RESLES and WMHI are present in high-altitude acclimatized individuals. However, these cerebral alterations are reversible within months at lowland.

Acute mountain sickness (AMS) occurs in up to 25% of unacclimatized persons who ascend to 3000 m and can result in high-altitude pulmonary edema (HAPE). MicroRNAs (miRs) can regulate gene expression at the post-transcriptional level. Hypoxia selectively disrupts endothelial tight junction complexes through a hypoxia-inducible factor-1α (HIF-1α)-dependent mechanism. Though increased HIF-1α expression is associated with adaptation and protection from AMS development in the early stage of hypoxia, a downstream effector of HIF-1α, VEGF, can induce overzealous endothelial barrier dysfunction, increase vascular permeability, and ultimately result in HAPE and high-altitude cerebral edema. We hypothesized that the fine-tuning of downstream effectors by miRs is paramount for the preservation of endothelial barrier integrity and the prevention of vascular leakage. We found that several miRs were up-regulated in healthy volunteers who were subjected to a 3100-m height. By reviewing the literature and using online bioinformatics prediction software, we specifically selected miR-424 for further investigation because it can modulate both HIF-1α and VEGF. Hypoxia-induced miR-424 overexpression is HIF-1α dependent, and miR-424 stabilized HIF-1α, decreased VEGF expression, and promoted vascular endothelial cadherin phosphorylation. In addition, hypoxia resulted in endothelial barrier dysfunction with increased permeability; miR-424 thus attenuated hypoxia-induced endothelial cell senescence and apoptosis. miR-322 knockout mice were susceptible to hypoxia-induced pulmonary vascular leakage. miR-322 mimics improved hypoxia-induced pulmonary vascular leakage in vivo . We conclude that several miRs were up-regulated in healthy adult volunteers subjected to hypobaric hypoxemia. miR-424/322 could modulate the HIF-1α-VEGF axis and prevent hypoxia-induced pulmonary vascular leakage under hypoxic conditions.-Tsai, S.-H., Huang, P.-H., Tsai, H.-Y., Hsu, Y.-J., Chen, Y.-W., Wang, J.-C., Chen, Y.-H., Lin, S.-J. Roles of the hypoximir microRNA-424/322 in acute hypoxia and hypoxia-induced pulmonary vascular leakage.

Background: Left cardiac pumping function determines the compensatory capacity of the cardiovascular system following acute high-altitude exposure. Variations in cardiac output (CO) at high altitude are inconsistent between individuals, and genetic susceptibility may play a crucial role. We sought to identify genetic causes of cardiac pumping function variations and describe the genotype-phenotype correlations., Methods: A total of 151 young male volunteers were recruited and transferred to Lhasa (3,700 m) from Chengdu (<500 m) by plane. Genetic information related to hypoxic signaling and cardiovascular-related pathways was collected before departure. Echocardiography was performed both before departure and 24 hr after arrival at high altitude., Results: Here we reported that PPARA variants were closely related to high-altitude cardiac function. The variants of rs6520015 C-allele and rs7292407 A-allele significantly increased the risk for cardiac pumping function reductions following acute high-altitude exposure. In addition, the individuals carrying haplotypes in PPARA, namely, rs135538 C-allele, rs4253623 A-allele, rs6520015 C-allele and rs7292407 A-allele (C-A-C-A), suffered a 7.27-fold risk for cardiac pumping function reduction (95% CI: 2.39-22.15, p = .0006) compared with those carrying the wild-type haplotype., Conclusions: This self-controlled study revealed that PPARA variations significantly increased the risk for cardiac pumping function reductions following acute high-altitude exposure, providing a potential predictive marker before high-altitude exposure and targets in mechanistic studies., (© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

The study of individuals at high-altitude (HA) exposure provides an important opportunity for unraveling physiological and psychological mechanism of brain underlying hypoxia condition. However, this has rarely been assessed longitudinally. We aim to explore the cognitive and cerebral microstructural alterations after chronic HA exposure. We recruited 49 college freshmen who immigrated to Tibet and followed up for 2 years. Control group consisted of 49 gender and age-matched subjects from sea level. Neuropsychological tests were also conducted to determine whether the subjects' cognitive function had changed in response to chronic HA exposure. Surface-based cortical and subcortical volumes were calculated from structural magnetic resonance imaging data, and tract-based spatial statistics (TBSS) analysis of white matter (WM) fractional anisotropy (FA) based on diffusion weighted images were performed. Compared to healthy controls, the high-altitude exposed individuals showed significantly lower accuracy and longer reaction times in memory tests. Significantly decreased gray matter volume in the caudate region and significant FA changes in multiple WM tracts were observed for HA immigrants. Furthermore, differences in subcortical volume and WM integration were found to be significantly correlated with the cognitive changes after 2 years' HA exposure. Cognitive functions such as working memory and psychomotor function were found to be impaired during chronic HA. Differences of brain subcortical volumes and WM integration between HA and sea-level participants indicated potential impairments in the brain structural modifications and microstructural integrity of WM tracts after HA exposure., (© 2019 Wiley Periodicals, Inc.)

Objective: This study aims to investigate the biological significance of heat shock protein (HSP70) in adaptation to high altitude hypoxia., Methods: Ninety male SD rats were randomly divided into 10 groups: Acute plateau hypoxia group (group 5) and chronic high altitude hypoxia group (group 3), and control group (group 2).Changes in HSP gene and HSP protein expression in brain tissues of SD rats at different altitudes were determined by Western blot and conventional RT-PCR, while an optical and transmission electron microscope was used to observe the cell structure changes of animal brain tissues., Results: HSP70 expression rapidly increased at high altitudes in SD rats under high-altitude hypoxia environments, and HSP70 increased with altitude. Morphological and structural damage in SD rats in each group increased with altitude., Conclusion: The rapid synthesis of HSP70 in heat shock response is beneficial for maintaining the normal physiological function of cells during hypoxia stress, and the amount of HSP70 production is positively correlated with hypoxia tolerance ability.

Background: Living at a high plateau in a very hostile environment and low oxygen levels often leads to the development of high-altitude polycythemia (HAPC) and gastric mucosal lesions caused by high-level reactive oxygen species (ROS). Hypoxia-inducible factor-1A (HIF-1A) helps maintain oxygen homeostasis by promoting the transcription of various genes and can be affected by ROS levels. To evaluate the molecular mechanism by which HAPC causes the gastric mucosal lesions, the expression of HIF-1A was measured in Tibetans with HAPC and in healthy subjects. Ultrastructural, histopathological, and immunohistochemical analyses were performed in the gastric tissues of both groups, and the expression of HIF-1A in the gastric mucosa was detected using qPCR and Western Blot., Results: The microvessel density and average diameter of gastric mucosal vessels were significantly greater in the HAPC patients than in the healthy subjects ( p < 0.05). The number of red blood cells in the gastric mucosa was also significantly higher in the HAPC group than in the healthy subjects ( p < 0.05). In addition, the density of the mitochondrial vacuoles and endoplasmic reticulum and pathological apoptosis were significantly increased in the gastric cells from HAPC patients compared to those from the healthy subjects. The levels of ROS and HIF-1A in the gastric mucosa were increased in HAPC patients compared to those in controls ( p < 0.05)., Conclusions: An increased level of HIF-1A was associated with HAPC development in the stomach of Tibetans living at a high altitude. ROS upregulated the levels of HIF-1A. Thus, ROS-mediated HIF-1A signaling transduction may be the mechanism associated with HAPC-induced gastric lesions.

MR imaging of high-altitude cerebral edema shows reversible WM edema, especially in the corpus callosum and subcortical WM. Recent studies have revealed hemosiderin deposition in WM long after high-altitude cerebral edema has resolved, providing a high-altitude cerebral edema "footprint." We wished to determine whether these microbleeds are present acutely and also describe the evolution of all MR imaging findings. In 8 patients with severe high-altitude cerebral edema, we obtained 26 studies: 18 with 3T and 8 with 1.5T scanners, during the acute stage, recovery, and follow-up in 7 patients and acutely in 1 patient. Imaging confirmed reversible cytotoxic and vasogenic WM edema that unexpectedly worsened the first week during clinical improvement before resolving. The 3T SWI, but not 1.5T imaging, showed extensive microbleeds extending beyond areas of edema seen acutely, which persisted and with time coalesced. These findings support cytotoxic and vasogenic edema leading to capillary failure/leakage in the pathophysiology of high-altitude cerebral edema and provide imaging correlation to the clinical course., (© 2019 by American Journal of Neuroradiology.)

Chronic hypobaric hypoxia induced muscle atrophy results in decreased physical performance at high altitude. Curcumin has been shown to have muscle sparing effects under cachectic conditions. However, the protective effects of curcumin under chronic hypobaric hypoxia have not been studied till now. Therefore, the present study aims at evaluating the effects of curcumin administration on muscle atrophy under chronic hypobaric hypoxia. Male Sprague Dawley rats were divided into four groups: Control (C)-normoxia exposed, Control Treated (CT)-normoxia exposed and administered with curcumin at a dose of 100 mg/kg body weight for 14 days, Hypoxia (H)-exposed to hypobaric hypoxia for 14 days and Hypoxia Treated (HT)-exposed to hypobaric hypoxia and administered with curcumin for 14 days. Oxidative stress, muscle protein degradation, proteolytic pathways, myosin heavy chain (MHC), CPK activity and muscle histology were performed in gastrocnemius muscle samples of the exposed rats. In addition, fatigue time on treadmill running was also evaluated to observe the effects of curcumin administration on physical performance of the rats. As previously shown, hypobaric hypoxia increased muscle protein degradation via upregulated calpain and ubiquitin-proteolytic pathways. An enhanced oxidative stress has been linked to upregulation of these pathways under hypoxic conditions. Curcumin administration resulted in reduced oxidative stress as well as reduced activity of the proteolytic pathways in HT group as compared to H group thereby resulting in reduced muscle protein degradation under hypobaric hypoxia. Histology of rat muscle revealed an increased number of muscle fibres in HT as compared to H group. Thus, increased number of muscle fibres and decreased muscle proteolysis following curcumin administration, lead to enhanced muscle mass under hypobaric hypoxia resulting in improved physical performance of the rats., (Copyright © 2018 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Hypobaric Hypoxia (HH) is well-known to cause cognitive impairment and synaptic dysfunction which results in neurodegeneration. Although the role of small conductance calcium-activated potassium channels (SK channels) has been reported in synaptic plasticity, cognition and different neurological disorders; however, the precise role of SK channels in HH-induced memory impairment remains yet to be explored. We, therefore, hypothesized the pivotal role of SK channels in HH-induced cognitive decline and investigated the SK channel expression during different duration of HH exposure (Control, 1, 3, 7 and 14 days) at mRNA and protein level in male Sprague-Dawley rats. Further the role of SK channels in spatial memory and neurodegeneration were explored by inhibiting SK channel through Apamin (a known SK channel blocker). Results from the present study revealed that acute exposure of HH for 3 days leads to significant increase in expression of SK1 and SK3 channels at mRNA and protein levels, which upon chronic exposure restored to normal. Remarkably, SK2 channel expression showed gradual increase from 3 days till 14 days. Immunohistochemical analysis revealed similar pattern in different regions of the hippocampus. Additionally, SK channel inhibition with Apamin prevented HH-induced neurodegeneration and memory impairment as evident from decreased number of Fluoro Jade-positive cells, pyknotic cells, and caspase-3 expression and improved performance in the Morris water maze task. Thus, the present study demonstrates that SK channels play a crucial role in HH-induced cognitive decline and neurodegeneration., (Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.)

The effects of hypoxia on the human organism has been considered doubly fascinating by the scientific community. The knowledge of the discrete mechanisms allowing the acclimatization both at genetic level or through the cell mediators production in addition to the macroscopic responses of the cardio-circulatory and ventilatory systems to a hypoxic environment has been progressively developed since the last century; moreover granting a safer stay in hypoxic conditions not only for the residents but also for the different cathegories of workers, sportsmen and tourists has been considered a worthy aim of the medical activity. The effects of hypoxia were simulated in laboratory by means of an induced low pressure environment (normobaric hypoxia) or tested on the subjects at different levels of altitude (hypobaric hypoxia). Far from describing all the physiological and pathological responses of the organism, in this review, the authors expose the state of the art in the knowledge of the responsiveness of the pulmonary circle to the acute or chronic hypoxic condition, its possible progression to the pulmonary arterial hypertension, the latter being more appropriately named High-Altitude Pulmonary Hypertension. The currently available therapeutic options in the treatment of High-Altitude Pulmonary Hypertension are also reviewed., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

We performed ultrastructural study of cerebral cortex mitochondria in rats with different tolerance to oxygen deficiency (low resistant and highly resistant specimens). Low resistant rats were characterized by the prevalence of mitochondria with lightened matrix due to the nondense packing of cristae. By contrast, mitochondria of highly resistant animals had the dense packing of cristae. The structure of mitochondria underwent adaptive changes at 14-10% O 2 in the inspired air. Under these conditions, structural characteristics of the cerebral cortex in hypoxia-sensitive rats resembled those in resistant animals. The decrease in O 2 concentration to 8% was accompanied by ultrastructural signs of mitochondrial damage, which correlated with de-energization of the cell and dysfunction of adaptive signaling systems. Ultrastructural features of cerebral cortex mitochondria in animals with low and high tolerance to acute oxygen deficiency confirm the hypothesis that they are associated with two different "functionaland-metabolic portraits".

As a typical model of hypoxia‑induced excessive erythrocytosis, high altitude polycythemia (HAPC) results in microcirculation disturbance, aggravates tissue hypoxia and results in a severe clinical outcome, without any effective intervention methods except for returning to an oxygen‑rich environment. The present study aimed to explore potential therapeutic targets which may participate in the recovery of HAPC by studying the mechanisms of reducing the hemoglobin (HB) concentration during re‑oxygenation. A total of 14 and 13 subjects were recruited over a 5,300 m distance and 5,170 m area. The patients were classified into HAPC or control groups based on their HB value. Plasma samples were collected on the day when they finished their stay in plateau for a year, and on the 180th day following their reaching in plain. Metabolic profiling was conducted by UPLC‑QTOF/MS. MetaboAnalyst platform was performed to explore the most perturbed metabolic pathways. A panel of differential metabolites were obtained in the recovery phase of HAPC and control groups. The present study identified the uniquely upregulated pentose phosphate pathway in HAPC subjects, along with a significantly decreased HB level. The findings were verified via a direct comparison between HAPC and control subjects at a high altitude. An increased pentose phosphate pathway was identified in control groups compared with HAPC subjects. An elevated pentose phosphate pathway may therefore participate in the recovery of HAPC, whereas a downregulated pentose phosphate pathway may contribute to hypoxia‑induced erythrocytosis. The results of the present study provide potential therapeutic strategies and novel insights into the pathogenesis of hypoxia‑induced polycythemia.

The purpose of the study was to identify the characteristics of apoptosis in the kidneys, ureters and bladder of fetuses and newborns in the modeling of chronic intrauterine hypoxia, acute postnatal hypoxia and mixed hypoxia. An experiment was conducted on WAG rats for modeling high altitude hypoxia. Experimental animals were divided into four groups: I - control - fetuses and newborns from healthy rats; II - modeling of chronic intrauterine hypoxia; III - modeling of acute postnatal hypoxia; IV - modeling of mixed hypoxia. The material of the study was the tissue of the kidneys, ureters and bladder of fetuses and newborns. In group I in the kidneys of fetuses the mean value of the number of p53-positive cells was 7.83±0.31, newborns - 5.40±0.28; in the ureters and bladder of fetuses - 5.77±0.29 and 6.97±0.32, newborns - 3.58±0.21 and 5.36±0.28. In the kidneys in group II the mean value of the number of p53-expressing cells in fetuses was 1.43±0.50, in newborns - 21.72±0.58; in group III in newborns - 15.03±0.63; in group IV in newborns - 33.33±0.72. The mean value of the number of p53-expressing cells in the ureters and bladder in group II in fetuses was 13.17±0.49 and 11.83±0.43, in newborns - 16.24±0.37 and 15.38±0.37; in group III in newborns - 7.25±0.27 and 8.68±0.32; in group IV in newborns - 19.63±0.31and 21.03±0.40. As the result of the study it was found that experimental hypoxia induced apoptotic processes in the kidneys, ureters and bladder of fetuses and newborns, the severity of which was moderate in the modeling of acute postnatal hypoxia, expressed in the modeling of chronic intrauterine hypoxia and strongly expressed in the modeling of mixed hypoxia. Under the influence of acute postnatal hypoxia, chronic intrauterine hypoxia and mixed hypoxia in the ureters and bladder of fetuses and newborns p53-positive cells were located evenly in all layers of the wall of these organs, whereas in the kidneys p53-positive cells prevailed in the tubular component. In the modeling of chronic intrauterine hypoxia apoptotic processes in the kidneys, ureters and bladder increased in newborns in comparison with fetuses.

We examined the pulmonary ultrastructure in tissue from two patients with high-altitude pulmonary edema (HAPE) by electron microscopy. In one case, we found that neutrophils were trapped in pulmonary capillary lumen of alveolar-capillary wall and part of the cytoplasm of a neutrophil protruded and adhered to the capillary endothelium. There were several degranulated vacuoles in the cytoplasm of the neutrophil. The pulmonary capillary wall was deformed, thickened, and swollen and there was evidence of degeneration. In another case, infiltration of neutrophils and macrophages, proliferation of type II pneumocytes, and numerous red blood cells were also observed in alveolar air space. These electron microscopic ultrastructural observations illustrate for the first time damage to the pulmonary alveolar-capillary barrier in lung tissue of humans with advanced HAPE.

High altitude cerebral edema (HACE) is a life-threatening illness that develops during the rapid ascent to high altitudes, but its underlying mechanisms remain unclear. Growing evidence has implicated inflammation in the susceptibility to and development of brain edema. In the present study, we investigated the inflammatory response and its roles in HACE in mice following high altitude hypoxic injury. We report that acute hypobaric hypoxia induced a slight inflammatory response or brain edema within 24h in mice. However, the lipopolysaccharide (LPS)-induced systemic inflammatory response rapidly aggravated brain edema upon acute hypobaric hypoxia exposure by disrupting blood-brain barrier integrity and activating microglia, increasing water permeability via the accumulation of aquaporin-4 (AQP4), and eventually leading to impaired cognitive and motor function. These findings demonstrate that hypoxia augments LPS-induced inflammation and induces the occurrence and development of cerebral edema in mice at high altitude. Here, we provide new information on the impact of systemic inflammation on the susceptibility to and outcomes of HACE., (Copyright © 2017 Elsevier Inc. All rights reserved.)

High altitude pulmonary edema (HAPE) occurs mainly under conditions such as high altitude, rapid ascent, or hypoxia. Previous studies suggest that ADRB2, GNB3, TH, and GSTP1 polymorphisms are associated with various lung diseases. We evaluated whether those polymorphisms are associated with the risk of HAPE in a Chinese Han population. ADRB2, GNB3, TH and GSTP1 polymorphisms were genotyped using a Sequenom MassARRAY. Logistic regression, adjusted for age and gender, was used to evaluate the association between the genotypes and the risk of HAPE by computing odds ratios (ORs) and 95% confidence intervals (95% CIs). The results revealed that GNB3 rs4963516 allele ''G'' (G vs T: OR = 0.70, 95% CI = 0.55-0.90, p = 0.006) was associated with HAPE risk. The ADRB2 rs1042718 alleles had a 1.29-fold (95%CI = 1.00-1.66; p = 0.045) increased risk of HAPE, and the GSTP1 rs749174 alleles had a 0.71-fold (95%CI = 0.52-0.99; p = 0.042) decreased risk of HAPE. Co-dominant and dominant models of GNB3 rs4963516 decreased the risk of HAPE (p = 0.023 and p = 0.008, respectively). Our results indicate GNB3 and GSTP1 polymorphisms may protect against HAPE progression, while ADRB2 polymorphisms are associated with an increased risk of HAPE.

Background: The synthetic peptide solnatide is a novel pharmacologic agent that reduces extravascular lung water, blunts reactive oxygen species production, and improves lung function due to its ability to directly activate the epithelial sodium channel. The goal of this study was to investigate the effect of solnatide in pulmonary edema induced by acute hypobaric hypoxia and exercise in rats, which is considered a model for high-altitude pulmonary edema., Methods: Sprague-Dawley rats were assigned to low-altitude control and eight treatment groups. Animals of all groups were subjected to exhaustive exercise in a hypobaric hypoxic environment simulating an altitude of 4,500 meters, followed by simulated ascent to 6,000 meters. After 48 h at 6,000 meters, rats were given sodium chloride, dexamethasone, aminophylline, p38 mitogen activated protein kinase inhibitor, and NOD-like receptor containing a pyrin domain 3 inhibitor, or one of three different doses of solnatide, once daily for 3 consecutive days. After 3 days, arterial blood gas, BAL fluid, lung water content, and histologic and ultra-microstructure analyses were performed. Tight junction protein occludin was assayed by using immunohistochemistry., Results: Rats treated with solnatide had significantly lower BAL fluid protein and lung water content than high-altitude control rats. Lungs of solnatide-treated rats were intact and showed less hemorrhage and disruption of the alveolar-capillary barrier than those of high-altitude control animals. Occludin expression was significantly higher in solnatide-treated animals, compared with high-altitude control, dexamethasone-, and aminophylline-treated animals., Conclusions: Solnatide reduced pulmonary edema, increased occludin expression, and improved gas-blood barrier function during acute hypobaric hypoxia and exercise in rats. These results provide a rationale for the clinical application of solnatide to patients with pulmonary edema and exposure to a high-altitude hypoxic environment., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

We observed patients with chronic mountain sickness (CMS) in our clinic who developed progressive neurological deterioration (encephalopathy) and we wished to investigate this. We studied nine such CMS patients, and compared them to 21 CMS patients without encephalopathy, and to 15 healthy control subjects without CMS. All 45 subjects lived permanently at 3200-4000 m. Measurements at 2260 m included CMS symptom score, multi-slice CT, perfusion CT, pulse oximetry (SpO 2 %), and hemoglobin concentration (Hb). One patient had MRI imaging but not CT; 5 had CSF pressure measurements. CMS subjects had lower SpO 2, higher Hb, higher brain blood density, lower mean cerebral blood flow (CBF), and significant cerebral circulatory delay compared to controls. The nine CMS subjects with neurological deterioration showed diffuse cerebral edema on imaging and more deranged cerebral hemodynamics. CSF pressure was elevated in those with edema. We conclude that cerebral edema, a previously unrecognized complication, may develop in CMS patients and cause encephalopathy. Contributing factors appear to be exaggerated polycythemia and hypoxemia, and lower and sluggish CBF compared to CMS patients without cerebral edema; but what triggers this complication is unknown. Recognition and treatment of this serious complication will help reduce morbidity and mortality from CMS.

Rapid ascent to high altitude commonly results in acute mountain sickness, and on occasion potentially fatal high-altitude cerebral edema. The exact pathophysiological mechanisms behind these syndromes remain to be determined. We report a study in which 12 subjects were exposed to a FiO 2  = 0.12 for 22 h and underwent serial magnetic resonance imaging sequences to enable measurement of middle cerebral artery velocity, flow and diameter, and brain parenchymal, cerebrospinal fluid and cerebral venous volumes. Ten subjects completed 22 h and most developed symptoms of acute mountain sickness (mean Lake Louise Score 5.4; p < 0.001 vs. baseline). Cerebral oxygen delivery was maintained by an increase in middle cerebral artery velocity and diameter (first 6 h). There appeared to be venocompression at the level of the small, deep cerebral veins (116 cm 3 at 2 h to 97 cm 3 at 22 h; p < 0.05). Brain white matter volume increased over the 22-h period (574 ml to 587 ml; p < 0.001) and correlated with cumulative Lake Louise scores at 22 h (p < 0.05). We conclude that cerebral oxygen delivery was maintained by increased arterial inflow and this preceded the development of cerebral edema. Venous outflow restriction appeared to play a contributory role in the formation of cerebral edema, a novel feature that has not been observed previously., (© The Author(s) 2016.)

A large proportion of lowlanders ascending to high-altitude (HA) show no signs of mountain sickness. Whether their brains have indeed suffered from HA environment and the persistent sequelae after return to lowland remain unknown. Thirty-one sea-level college students, who had a 30-day teaching on Qinghai-Tibet plateau underwent MRI scans before, during, and two months after HA exposure. Brain volume, cortical structures, and white matter microstructure were measured. Besides, serum neuron-specific enolase (NSE), C-reactive protein, and interleukin-6 and neuropsychiatric behaviors were tested. After 30-day HA exposure, the gray and white matter volumes and cortical surface areas significantly increased, with cortical thicknesses and curvatures changed in a wide spread regions; Anisotropy decreased with diffusivities increased in multiple sites of white matter tracts. Two months after HA exposure, cortical measurements returned to basal level. However, increased anisotropy with decreased diffusivities was observed. Behaviors and serum inflammatory factor did not significant changed during three time-point tests. NSE significantly decreased during HA but increased after HA exposure. Results suggest brain swelling occurred in people without neurological signs at HA, but no negative sequelae in cortical structures and neuropsychiatric functions were left after the return to lowlands. Reoxygenation changed white matter microstructure.

The aim of the present study was to examine cerebral vasoconstriction in patients with chronic high altitude disease [cerebrovascular reactivity (CVR)], and to evaluate differences in alterations of brain vascular contractile reactivity of chronic mountain sickness (CMS) patients and healthy controls. Alterations of endothelin (ET) and its receptor, as well as endothelial nitric oxide synthase (eNOS) levels in the plasma were examined to determine the cerebral reservation capacities in CMS patients. Transcranial Doppler ultrasound and carbon dioxide analysis methods were used to detect the CVR variances. At the same time, enzyme‑linked immunosorbent assay approaches were utilized to detect the ET and ET B receptor and the eNOS levels in serum of the CMS patients and healthy controls. CVR and CVRI levels in CMS patients were lower than those of the healthy control subjects and the difference was statistically significant (P<0.05). By contrast, eNOS and ET‑1 levels were not statistically significant for CMS and healthy controls (P>0.05). However, the ET receptor concentration level was higher in CMS than the healthy controls. Thus, ET‑1 may not be a direct etiological variation but may play compensatory roles in CMS patients. The results of the study may provide scientific clues for the prevention and treatment of CMS with higher blood coagulation states of cerebral infarction in patients with chronic high altitude disease.

Villafuerte, Francisco C., and Noemí Corante. Chronic mountain sickness: clinical aspects, etiology, management, and treatment. High Alt Med Biol. 17:61-69, 2016.-Millions of people worldwide live at a high altitude, and a significant number are at risk of developing Chronic Mountain Sickness (CMS), a progressive incapacitating syndrome caused by lifelong exposure to hypoxia. CMS is characterized by severe symptomatic excessive erythrocytosis (EE; Hb ≥19 g/dL for women and Hb ≥21 g/dL for men) and accentuated hypoxemia, which are frequently associated with pulmonary hypertension. In advanced cases, the condition may evolve to cor pulmonale and congestive heart failure. Current knowledge indicates a genetic predisposition to develop CMS. However, there are important risk factors and comorbidities that may trigger and aggravate the condition. Thus, appropriate medical information on CMS is necessary to provide adequate diagnosis and healthcare to high-altitude inhabitants. After reviewing basic clinical aspects of CMS, including its definition, diagnosis, and common clinical findings, we discuss aspects of its etiology, and address its epidemiology, risk factors, and treatment.

High altitude hypobaric hypoxia (HH) affects prefrontal cognitive and executive functions. Guanfacine, alpha 2A adrenoceptor agonist ameliorates the neurological outcomes of high altitude exposure and associated prefrontal neurodegeneration. However, the molecular mechanism underlying the neuroprotective effect of guanfacine following HH remains elusive. Altered balance of pro and anti-apoptotic proteins have been implicated in the beneficial effect of guanfacine to enhance neuronal survival. We examined the effects of guanfacine on expression of some key neurotropic and cytoskeletal proteins following HH. Male rats were exposed to simulated altitude of 7620 m and received an intramuscular injection of either saline or guanfacine at a dose of 1mg/kg for 7 consecutive days. Differential expression of desired proteins was evaluated in layer II of medial prefrontal cortex (PFC) by biochemical and immunohistochemical assays. Guanfacine treatment significantly increased the expression of BDNF in layer II of the medial PFC during normoxia and HH. Moreover, there was a negative correlation of this neurotropic factor with neurodegeneration of pyramidal cells present in this layer of medial PFC. We found a significant decrease in Caspase3 and Bax while a significant increase in Bcl2 with guanfacine treatment during HH. Further, change in Bax to Bcl2 ratio was in correlation with Caspase3 expression in layer II of the medial PFC, indicating that Caspase3 is responsible for Bcl2 cleavage and hence modulation of apoptosis. Guanfacine treatment induced a marked and significant increase in MAP2 and Spinophilin expression in dendritic arbors and spines respectively. Interestingly, alteration in these cytoskeletal proteins was accompanied by simultaneous changes in morphological parameters of dendrites in layer II of medial PFC. Guanfacine modulates the neurotropic, cytoskeletal, pro and anti-apoptotic protein expression in medial PFC under HH and therefore serve as a countermeasure in the amelioration of HH induced alteration in these proteins., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Purpose: Repetitive obstruction of larynx during sleep can lead to daytime pulmonary hypertension and alterations in right ventricular morphology and function in a small fraction of obstructive sleep apnea syndrome (OSAS) patients. Environmental effects, particularly high altitude, can modify the effects of OSAS on pulmonary circulation, since altitude-related hypoxia is related with pulmonary vasoconstriction. This potential interaction, however, was not investigated in previous studies., Methods: A total of 41 newly diagnosed OSAS patients were included in this study after pre-enrolment screening. Two-dimensional, three-dimensional, and Doppler echocardiographic data were collected after polysomnographic verification of OSAS. Three-dimensional echocardiograms were analyzed to calculate right ventricular volumes, volume indices, and ejection fraction., Results: Systolic pulmonary artery pressure (38.35 ± 8.60 vs. 30.94 ± 6.47 mmHg; p = 0.002), pulmonary acceleration time (118.36 ± 16.36 vs. 103.13 ± 18.42 ms; p = 0.001), right ventricle (RV) end-diastolic volume index (48.15 ± 11.48 vs. 41.48 ± 6.45 ml; p = 0.009), and RV end-systolic volume index (26.50 ± 8.11 vs. 22.15 ± 3.85; p = 0.01) were significantly higher in OSAS patients, with similar RV ejection fraction (EF) between groups. No significant differences were noted in other two-dimensional, Doppler or speckle-tracking strain, measurements. Both RVEF and pulmonary acceleration time were predictors of disease severity., Conclusions: A greater degree of RV structural remodeling and higher systolic pulmonary pressure were observed in OSAS patients living at high altitude compared to healthy highlanders. The reversibility of these alterations with treatment remains to be studied.

High-altitude illness is a result of prolonged high-altitude exposure of unacclimatized individuals. The illness is seen in the form of acute mountain sickness (AMS) which if not treated leads to potentially life-threatening high altitude pulmonary oedema and high-altitude cerebral oedema. Medical problems are caused by hypobaric hypoxia stimulating hypoxia-inducible factor (HIF) release. As a result, the central nervous system, circulation and respiratory system function impairment occurs. The most important factor in AMS treatment is acclimatization, withdrawing further ascent and rest or beginning to descent; oxygen supplementation, and pharmacological intervention, and, if available, a portable hyperbaric chamber. Because of the popularity of high-mountain sports and tourism better education of the population at risk is essential.

Studies of high-altitude populations, and in particular of maladapted subgroups, may provide important insight into underlying mechanisms involved in the pathogenesis of hypoxemia-related disease in general. Chronic mountain sickness (CMS) is a major public health problem in mountainous regions of the world affecting many millions of high-altitude dwellers. It is characterized by exaggerated chronic hypoxemia, erythrocytosis, and mild pulmonary hypertension. In later stages these patients often present with right heart failure and are predisposed to systemic cardiovascular disease, but the underlying mechanisms are poorly understood. Here, we present recent new data providing insight into underlying mechanisms that may cause these complications.