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To compensate for decreased oxygen partial pressure, high-altitude residents increase hemoglobin concentrations [Hb]. The elevation varies between world regions, posing problems in defining cutoff values for anemia or polycythemia. The currently used altitude adjustments (World Health Organization [WHO]), however, do not account for regional differences. Data from The Demographic and Health Survey (DHS) Program were analyzed from 32 countries harboring >4% of residents at altitudes above 1000 m. [Hb]-increase, (ΔHb/km altitude) was calculated by linear regression analysis. Tables show 95% reference intervals (RIs) for different altitude ranges, world regions, and age groups. The prevalence of anemia and polycythemia was calculated using regressions in comparison to WHO adjustments. The most pronounced Δ[Hb]/km was found in East Africans and South Americans while [Hb] increased least in South/South-East Asia. In African regions and Middle East, [Hb] was decreased in some altitude regions showing inconsistent changes in different age groups. Of note, in all regions, the Δ[Hb]/km was lower in children than in adults, and in the Middle East, it was even negative. Overall, the Δ[Hb]/km from our analysis differed from the region-independent adjustments currently suggested by the WHO resulting in a lower anemia prevalence at very high altitudes. The distinct patterns of Δ[Hb] with altitude in residents from different world regions imply that one single, region-independent correction factor for altitude is not be applicable for diagnosing abnormal [Hb]. Therefore, we provide regression coefficients and reference-tables that are specific for world regions and altitude ranges to improve diagnosing abnormal [Hb]., Competing Interests: MUM is a HemaSphere editor. The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

Fast changes in environmental oxygen availability translate into shifts in mitochondrial free radical production. An increase in intraerythrocytic reduced glutathione (GSH) during deoxygenation would support the detoxification of exogenous oxidants released into the circulation from hypoxic peripheral tissues. Although reported, the mechanism behind this acute oxygen-dependent regulation of GSH in red blood cells remains unknown. This study explores the role of hemoglobin (Hb) in the oxygen-dependent modulation of GSH levels in red blood cells. We have demonstrated that a decrease in Hb O 2 saturation to 50% or less observed in healthy humans while at high altitude, or in red blood cell suspensions results in rising of the intraerythrocytic GSH level that is proportional to the reduction in Hb O 2 saturation. This effect was not caused by the stimulation of GSH de novo synthesis or its release during deglutathionylation of Hb's cysteines. Using isothermal titration calorimetry and in silico modeling, we observed the non-covalent binding of four molecules of GSH to oxy-Hb and the release of two of them upon deoxygenation. Localization of the GSH binding sites within the Hb molecule was identified. Oxygen-dependent binding of GSH to oxy-Hb and its release upon deoxygenation occurred reciprocally to the binding and release of 2,3-bisphosphoglycerate. Furthermore, noncovalent binding of GSH to Hb moderately increased Hb oxygen affinity. Taken together, our findings have identified an adaptive mechanism by which red blood cells may provide an advanced antioxidant defense to respond to oxidative challenges immediately upon deoxygenation., Competing Interests: Declaration of competing interest The authors of the manuscript REDOX-D-22-00013 have no conflict of interests to declare., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Pulmonary hypertension (PH) is characterized by progressive obstruction of pulmonary arteries owing to inflammatory processes, cellular proliferation, and extracellular matrix deposition and vasoconstriction. As treatment options are limited, we studied gene transfer of an inducible nitric oxide synthase (iNOS) using adeno-associated virus (AAV) vectors specifically targeted at endothelial cells of pulmonary vessels in a murine model of PH. Adult mice were intravenously injected with AAV vectors expressing iNOS. Mice were subjected to hypoxia for 3 weeks and killed afterward. We found elevated levels of iNOS both in lung tissue and pulmonary endothelial cells in hypoxic controls that could be further increased by AAV-mediated iNOS gene transfer. This additional increase in iNOS was associated with decreased wall thickness of pulmonary vessels, less macrophage infiltration, and reduced molecular markers of fibrosis. Taken together, using a tissue-targeted approach, we show that AAV-mediated iNOS overexpression in endothelial cells of the pulmonary vasculature significantly decreases vascular remodeling in a murine model of PH, suggesting upregulation of iNOS as promising target for treatment of PH.

Inflammation and hypoxia impair alveolar barrier tightness, inhibit Na- and fluid reabsorption, and cause edema. We tested whether stimulated alveolar macrophages affect alveolar Na-transport and whether hypoxia aggravates the effects of inflammation, and tested for involved signaling pathways. Primary rat alveolar type II cells (rA2) were co-cultured with rat alveolar macrophages (NR8383) or treated with NR8383-conditioned media after stimulation with lipopolysaccharide (LPS; 1 µg/mL) and exposed to normoxia and hypoxia (1.5% O 2 ). LPS caused a fast, transient increase in TNFα and IL-6 mRNA in macrophages and a sustained increase in inducible nitric oxide synthase (NOS2) mRNA in macrophages and in rA2 cells resulting in elevated nitrite levels and secretion of TNF-α and IL-6 into culture media. In normoxia, 24 h of LPS treated NR8383 decreased the transepithelial electrical resistance (TEER) of co-cultures, of amiloride-sensitive short circuit current (ISC Δamil ); whereas Na/K-ATPase activity was not affected. Inhibition was also seen with conditioned media from LPS-stimulated NR8383 on rA2, but was less pronounced after dialysis to remove small molecules and nitrite. The effect of LPS-stimulated macrophages on TEER and Na-transport was fully prevented by the iNOS-inhibitor L-NMMA applied to co-cultures and to rA2 mono-cultures. Hypoxia in combination with LPS-stimulated NR8383 totally abolished TEER and ISCΔamil. These results indicate that the LPS-stimulation of alveolar macrophages impairs alveolar epithelial Na-transport by NO-dependent mechanisms, where part of the NO is produced by rA2 induced by signals from LPS stimulated alveolar macrophages.

Hypoxia is associated with increased erythropoietin (EPO) release to drive erythropoiesis. At high altitude, EPO levels first increase and then decrease, although erythropoiesis remains elevated at a stable level. The roles of hypoxia and related EPO adjustments are not fully understood, which has contributed to the formulation of the theory of neocytolysis. We aimed to evaluate the role of oxygen exclusively on erythropoiesis, comparing in vitro erythroid differentiation performed at atmospheric oxygen, a lower oxygen concentration (three percent oxygen) and with cultures of erythroid precursors isolated from peripheral blood after a 19-day sojourn at high altitude (3450 m). Results highlight an accelerated erythroid maturation at low oxygen and more concave morphology of reticulocytes. No differences in deformability were observed in the formed reticulocytes in the tested conditions. Moreover, hematopoietic stem and progenitor cells isolated from blood affected by hypoxia at high altitude did not result in different erythroid development, suggesting no retention of a high-altitude signature but rather an immediate adaptation to oxygen concentration. This adaptation was observed during in vitro erythropoiesis at three percent oxygen by a significantly increased glycolytic metabolic profile. These hypoxia-induced effects on in vitro erythropoiesis fail to provide an intrinsic explanation of the concept of neocytolysis.

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).)

Aims: Total haemoglobin mass (tot-Hb) increases during high-altitude acclimatization. Normalization of tot-Hb upon descent is thought to occur via neocytolysis, the selective destruction of newly formed erythrocytes. Because convincing experimental proof of neocytolysis is lacking, we performed a prospective study on erythrocyte survival after a stay at the Jungfraujoch Research Station (JFJRS; 3450 m)., Methods: Newly formed erythrocytes of 12 male subjects (mean age 23.3 years) were age cohort labelled in normoxia (110 m) and during a 19-day high-altitude sojourn by ingestion of 13 C2- and 15 N-labelled glycine respectively. Elimination dynamics for erythrocytes produced in normoxia and at high altitude were measured by isotope ratio mass spectrometry of haem, by determining tot-Hb, reticulocyte counts, erythrocyte membrane protein 4.1a/4.1b ratio and by mathematical modelling., Results: Tot-Hb increased by 4.7% ± 2.7% at high altitude and returned to pre-altitude values within 11 days after descent. Elimination of 13 C- (normoxia) and 15 N- (high altitude) labelled erythrocytes was not different. Erythropoietin levels and counts of CD71-positive reticulocytes decreased rapidly after descent. The band 4.1a/4.1b ratio decreased at altitude and remained low for 3-4 days after descent and normalized slowly. There was no indication of haemolysis., Conclusion: We confirm a rapid normalization of tot-Hb upon descent. Based on the lack of accelerated removal of age cohorts of erythrocytes labelled at high altitude, on patterns of changes in reticulocyte counts and of the band 4.1a/4.1b ratio and on modelling, this decrease did not occur via neocytolysis, but by a reduced rate of erythropoiesis along with normal clearance of senescent erythrocytes., (© 2021 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.)

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is one of the most common chronic disorders with limited therapeutic options. However, the pathogenesis of CRSwNP remains poorly understood., Objective: We sought to determine the role of abnormalities in nasal epithelial ion transport in primary epithelial cultures and patients with CRSwNP., Methods: We studied epithelial ion transport and transcript levels of the Cl - channels cystic fibrosis transmembrane conductance regulator and transmembrane protein 16A (TMEM16A) in human primary nasal epithelial cultures of patients with CRSwNP and healthy controls. Furthermore, we determined expression levels of proinflammatory cytokines that have been implicated in the regulation of epithelial ion channels (IL-1β, INF-γ, TNF-α, IL-13) and studied effects of the key T H 2 signaling molecule IL-13 in CRSwNP and control nasal epithelial cultures. Finally, we measured in vivo nasal potential difference to compare epithelial ion transport in patients with CRSwNP and controls., Results: Bioelectric studies demonstrated that Ca 2+ -activated Cl - secretion was reduced in CRSwNP versus control nasal epithelial cultures. Transcript levels of IL-13 and the Ca 2+ -activated Cl - channel TMEM16A were increased in CRSwNP cultures. Stimulation with IL-13 increased TMEM16A expression further and restored Ca 2+ -activated Cl - secretion in CRSwNP cultures. Nasal potential difference measurements demonstrated reduced Ca 2+ -activated Cl - transport in patients with CRSwNP versus controls., Conclusions: This study demonstrates that TMEM16A-mediated Ca 2+ -activated Cl - secretion is reduced in primary nasal epithelial cultures and nasal epithelia of patients with CRSwNP. Our data suggest that the Ca 2+ -activated Cl - channel TMEM16A may be implicated in the pathogenesis and serve as a novel therapeutic target in patients with CRSwNP., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Increasing the hemoglobin (Hb) concentration is a major mechanism adjusting arterial oxygen content to decreased oxygen partial pressure of inspired air at high altitude. Approximately 5% of the world's population living at altitudes higher than 1,500 m shows this adaptive mechanism. Notably, there is a wide variation in the extent of increase in Hb concentration among different populations. This short review summarizes available information on Hb concentrations of high-altitude residents living at comparable altitudes (3,500-4,500 m) in different regions of the world. An increased Hb concentration is found in all high-altitude populations. The highest mean Hb concentration was found in adult male Andean residents and in Han Chinese living at high altitude, whereas it was lowest in Ethiopians, Tibetans, and Sherpas. A lower plasma volume in Andean high-altitude natives may offer a partial explanation. Indeed, male Andean high-altitude natives have a lower plasma volume than Tibetans and Ethiopians. Moreover, Hb values were lower in adult, nonpregnant females than in males; differences between populations of different ancestry were less pronounced. Various genetic polymorphisms were detected in high-altitude residents thought to favor life in a hypoxic environment, some of which correlate with the relatively low Hb concentration in the Tibetans and Ethiopians, whereas differences in angiotensin-converting enzyme allele distribution may be related to elevated Hb in the Andeans. Taken together, these results indicate different sensitivity of oxygen dependent control of erythropoiesis or plasma volume among populations of different geographical ancestry, offering explanations for differences in the Hb concentration at high altitude.

Reabsorption of excess alveolar fluid is driven by vectorial Na + -transport across alveolar epithelium, which protects from alveolar flooding and facilitates gas exchange. Hypoxia inhibits Na + -reabsorption in cultured cells and in-vivo by decreasing activity of epithelial Na + -channels (ENaC), which impairs alveolar fluid clearance. Inhibition also occurs during in-vivo hypoxia in humans and laboratory animals. Signaling mechanisms that inhibit alveolar reabsorption are poorly understood. Because cellular adaptation to hypoxia is regulated by hypoxia-inducible transcription factors (HIF), we tested whether HIFs are involved in decreasing Na + -transport in hypoxic alveolar epithelium. Expression of HIFs was suppressed in cultured rat primary alveolar epithelial cells (AEC) with shRNAs. Hypoxia (1.5% O 2 , 24 h) decreased amiloride-sensitive transepithelial Na + -transport, decreased the mRNA expression of α-, β-, and γ-ENaC subunits, and reduced the amount of αβγ-ENaC subunits in the apical plasma membrane. Silencing HIF-2α partially prevented impaired fluid reabsorption in hypoxic rats and prevented the hypoxia-induced decrease in α- but not the βγ-subunits of ENaC protein expression resulting in a less active form of ENaC in hypoxic AEC. Inhibition of alveolar reabsorption also caused pulmonary vasoconstriction in ventilated rats. These results indicate that a HIF-2α-dependent decrease in Na + -transport in hypoxic alveolar epithelium decreases alveolar reabsorption. Because susceptibles to high-altitude pulmonary edema (HAPE) have decreased Na + -transport even in normoxia, inhibition of alveolar reabsorption by hypoxia at high altitude might further impair alveolar gas exchange. Thus, aggravated hypoxemia might further enhance hypoxic pulmonary vasoconstriction and might subsequently cause HAPE., (© The Author(s) 2020.)

Residents at high altitude cope with decreasing inspiratory oxygen partial pressure by stimulating erythropoiesis. The increase in hemoglobin levels requires high amounts of additional iron supplied from the diet. Here, we review available data on how iron metabolism adapts when living in a hypoxic environment. Our analysis reveals that long-term adaptation to high altitude enables healthy individuals to maintain their iron stores within the physiological range despite elevated requirements for erythropoiesis. However, in vulnerable populations with increased iron demand (e.g., pregnant women or exercising individuals), iron stores are less likely to be replenished quickly when living at high altitude. Future studies need to address whether different ethnicities have acquired genetic mechanisms to adapt to the elevated iron demand for erythropoiesis at high altitude.

Purpose: Ascent to high altitude increases right ventricular (RV) afterload and decreases myocardial energy supply. This study evaluates physiologic variables and comprehensive echocardiographic indices of RV and right atrial (RA) function following rapid ascent to high altitude., Methods: Fifty healthy volunteers actively ascended from 1130 to 4559 m in < 22 h. All participants underwent 2D echocardiography during baseline examination at low altitude (424 m) and at three study time-points (7, 20 and 44 h) after arrival at high altitude. In addition to systolic pulmonary artery pressure (sPAP), comprehensive 2D planimetric-, tissue Doppler- and speckle-tracking-derived strain indices of RA and RV function were obtained., Results: sPAP increased from baseline (24 ± 4 mmHg) to the first altitude examination (39 ± 8 mmHg, p < 0.001) and remained elevated during the following 44 h. Global RV function did not change. RA reservoir strain showed a trend towards increase from baseline (50.2 ± 12.1%) to the first altitude examination (53.8 ± 11.0%, p = 0.07) secondary to a significant increase of RA contraction strain (19.2 ± 6.4 vs. 25.4 ± 9.6%, p < 0.001). Volumetric RA data largely paralleled RA strain results and RA active emptying volume was increased throughout the 44 h stay at high altitude., Conclusion: Active and rapid ascent of healthy individuals to 4559 m is associated with an increased contractile performance of the RA that compensates for the increased workload of the RV.

Background: The stress of high altitude alters vascular permeability, which may be related to structural changes in the endothelial glycocalyx. We aimed to study these changes by measuring plasma concentrations of several glycocalyx components upon exposure to high altitude. Methods: Plasma collected from 17 subjects at low altitude (423 m) and at three time points (7, 20, and 44 hours) after rapid ascent to high altitude (4559 m) were evaluated for concentrations of three glycocalyx components: syndecan-1, intercellular adhesion molecule-1 (ICAM-1), and heparan sulfate. Vital signs and echocardiographic measurement of systolic pulmonary artery pressure (sPAP) and cardiac output were also obtained at low and high altitudes. Results: Mean age of the study population was 35.5 ± 11.2 years with a body mass index of 22.7 ± 2.5 kg/m 2 . Concentrations of ICAM-1 and heparan sulfate increased from baseline to 7 hours after arrival at high altitude; the ICAM-1 rise persisted at 20 hours. Syndecan-1 concentrations were increased only at 44 hours. Increased ICAM-1 concentrations correlated with sPAP and peripheral edema. Elevations in heparan sulfate appeared to correlate with acute mountain sickness (AMS). Conclusions: Levels of circulating glycocalyx components increase after exposure to high altitude and may correlate with AMS. Measuring plasma concentrations of various glycocalyx components could serve as a useful tool for further evaluation of vascular endothelial injury and repair in illness at high altitude.

Background: Exaggerated pulmonary arterial hypertension (PAH) is a hallmark of high-altitude pulmonary edema (HAPE). The objective of this study was therefore to investigate genetic predisposition to HAPE by analyzing PAH candidate genes in a HAPE-susceptible (HAPE-S) family and in unrelated HAPE-S mountaineers. Materials and Methods: Eight family members and 64 mountaineers were clinically and genetically assessed using a PAH-specific gene panel for 42 genes by next-generation sequencing. Results: Two otherwise healthy family members, who developed re-entry HAPE at 3640 m during childhood, carried a likely pathogenic missense mutation (c.1198T>G p.Cys400Gly) in the Janus Kinase 2 ( JAK2 ) gene. One of them progressed to a mild form of PAH at the age of 23 years. In two of the 64 HAPE-S mountaineers likely pathogenic variants have been detected, one missense mutation in the Cytochrome P1B1 gene, and a deletion in the Histidine-Rich Glycoprotein ( HRG ) gene. Conclusions: This is the first study identifying an inherited missense mutation of a gene related to PAH in a family with re-entry HAPE showing a progression to borderline PAH in the index patient. Likely pathogenic variants in 3.1% of HAPE-S mountaineers suggest a genetic predisposition in some individuals that might be linked to PAH signaling pathways.

Individuals ascending rapidly to altitudes >2500 m may develop symptoms of acute mountain sickness (AMS) within a few hours of arrival and/or high-altitude pulmonary edema (HAPE), which occurs typically during the first three days after reaching altitudes above 3000-3500 m. Both diseases have distinct pathologies, but both present with a pronounced decrease in oxygen saturation of hemoglobin in arterial blood (SO 2 ). This raises the question of mechanisms impairing the diffusion of oxygen (O 2 ) across the alveolar wall and whether the higher degree of hypoxemia is in causal relationship with developing the respective symptoms. In an attempt to answer these questions this article will review factors affecting alveolar gas diffusion, such as alveolar ventilation, the alveolar-to-arterial O 2 -gradient, and balance between filtration of fluid into the alveolar space and its clearance, and relate them to the respective disease. The resultant analysis reveals that in both AMS and HAPE the main pathophysiologic mechanisms are activated before aggravated decrease in SO 2 occurs, indicating that impaired alveolar epithelial function and the resultant diffusion limitation for oxygen may rather be a consequence, not the primary cause, of these altitude-related illnesses.

Decreased oxygen availability at high altitude requires physiological adjustments allowing for adequate tissue oxygenation. One such mechanism is a slow increase in the hemoglobin concentration ([Hb]) resulting in elevated [Hb] in high-altitude residents. Diagnosis of anemia at different altitudes requires reference values for [Hb]. Our aim was to establish such values based on published data of residents living at different altitudes by applying meta-analysis and multiple regressions. Results show that [Hb] is increased in all high-altitude residents. However, the magnitude of increase varies among the regions analyzed and among ethnic groups within a region. The highest increase was found in residents of the Andes (1 g/dL/1000 m), but this increment was smaller in all other regions of the world (0.6 g/dL/1000 m). While sufficient data exist for adult males and females showing that sex differences in [Hb] persist with altitude, data for infants, children, and pregnant women are incomplete preventing such analyses. Because WHO reference values were originally based on [Hb] of South American people, we conclude that individual reference values have to be defined for ethnic groups to reliably diagnose anemia and erythrocytosis in high-altitude residents. Future studies need to test their applicability for children of different ages and pregnant women., (© 2019 New York Academy of Sciences.)

Hypoxia challenges left ventricular (LV) function due to reduced energy supply. Conflicting results exist whether high-altitude exposure impairs LV diastolic function and thus contributes to the high altitude-induced increase in systolic pulmonary artery pressure (sPAP) and reduction in stroke volume (SV). This study aimed to assess LV diastolic function, LV end-diastolic pressure (LVEDP), and LA mechanics using comprehensive echocardiographic imaging in healthy volunteers at 4559 m. Fifty subjects performed rapid (<20 hours) and active ascent from 1130 m to 4559 m (high). All participants underwent echocardiography during baseline examination at 424 m (low) as well as 7, 20 and 44 hours after arrival at high altitude. Heart rate (HR), sPAP, and comprehensive volumetric- and Doppler- as well as speckle tracking-derived LA strain parameters were obtained to assess LV diastolic function, LA mechanics, and LVEDP in a multiparametric approach. Data for final analyses were available in 46 subjects. HR (low: 64 ± 11 vs high: 79 ± 14 beats/min, P < 0.001) and sPAP (low: 24.4 ± 3.8 vs high: 38.5 ± 8.2 mm Hg, P < 0.001) increased following ascent and remained elevated at high altitude. Stroke volume (low: 64.5 ± 15.0 vs high: 58.1 ± 16.4 mL, P < 0.001) and EDV decreased following ascent and remained decreased at high altitude due to decreased LV passive filling volume, whereas LA mechanics were preserved. There was no case of LV diastolic dysfunction or increased LVEDP estimates. In summary, this study shows that rapid and active ascent of healthy individuals to 4559 m impairs passive filling and SV of the LV. These alterations were not related to changes in LV and LA mechanics., (© 2018 The Authors. Scandinavian Journal of Medicine & Science In Sports Published by John Wiley & Sons Ltd.)

Glioma growth is often accompanied by a hypoxic microenvironment favorable for the induction and maintenance of the glioma stem cell (GSC) phenotype. Due to the paucity of cell models of Isocitrate Dehydrogenase 1 mutant (IDH1 mut ) GSCs, biology under hypoxic conditions has not been sufficiently studied as compared to IDH1 wildtype (IDH1 wt ) GSCs. We therefore grew well-characterized IDH1 mut ( n = 4) and IDH1 wt ( n = 4) GSC lines under normoxic (20%) and hypoxic (1.5%) culture conditions and harvested mRNA after 72 h. Transcriptome analyses were performed and hypoxia regulated genes were further analyzed using the expression and clinical data of the lower grade glioma cohort of The Cancer Genome Atlas (LGG TCGA) in a confirmatory approach and to test for possible survival associations. Results show that global expression changes were more pronounced in IDH1 wt than in IDH1 mut GSCs. However, when focusing on known hypoxia-regulated gene sets, enrichment analyses showed a comparable regulation in both IDH1 mut and IDH1 wt GSCs. Of 272 significantly up-regulated genes under hypoxic conditions in IDH1 mut GSCs a hypoxia-related survival score (HRS-score) of five genes ( LYVE1 , FAM162A , WNT6 , OTP , PLOD1 ) was identified by the Least Absolute Shrinkage and Selection Operator (LASSO) algorithm which was able to predict survival independent of age, 1p19q co-deletion status and WHO grade (II vs. III) in the LGG TCGA cohort and in the Rembrandt dataset. Altogether, we were able to identify and validate a novel hypoxia-related survival score in IDH1 mut GSCs consisting of five hypoxia-regulated genes which was significantly associated with patient survival independent of known prognostic confounders.

Rationale: The combination of the CFTR (cystic fibrosis transmembrane conductance regulator) corrector lumacaftor with the potentiator ivacaftor has been approved for the treatment of patients with cystic fibrosis homozygous for the Phe508del CFTR mutation. The phase 3 trials examined clinical outcomes but did not evaluate CFTR function in patients., Objectives: To examine the effect of lumacaftor-ivacaftor on biomarkers of CFTR function in Phe508del homozygous patients with cystic fibrosis aged 12 years and older., Methods: This prospective observational study assessed clinical outcomes including FEV 1 % predicted and body mass index, and CFTR biomarkers including sweat chloride concentration, nasal potential difference, and intestinal current measurement before and 8-16 weeks after initiation of lumacaftor-ivacaftor., Measurements and Main Results: A total of 53 patients were enrolled in the study, and 52 patients had baseline and follow-up measurements. After initiation of lumacaftor-ivacaftor sweat chloride concentrations were reduced by 17.8 mmol/L (interquartile range [IQR], -25.9 to -6.1; P < 0.001), nasal potential difference showed partial rescue of CFTR function in nasal epithelia to a level of 10.2% (IQR, 0.0-26.1; P < 0.011), and intestinal current measurement showed functional improvement in rectal epithelia to a level of 17.7% of normal (IQR, 10.8-29.0; P < 0.001). All patients improved in at least one CFTR biomarker, but no correlations were found between CFTR biomarker responses and clinical outcomes., Conclusions: Lumacaftor-ivacaftor results in partial rescue of Phe508del CFTR function to levels comparable to the lower range of CFTR activity found in patients with residual function mutations. Functional improvement was detected even in the absence of short-term improvement of FEV 1 % predicted and body mass index. Clinical trial registered with www.clinicaltrials.gov (NCT02807415).

Living, working and exercising in extreme terrestrial environments are challenging tasks even for healthy humans of the modern new age. The issue is not just survival in remote environments but rather the achievement of optimal performance in everyday life, occupation, and sports. Various adaptive biological processes can take place to cope with the specific stressors of extreme terrestrial environments like cold, heat, and hypoxia (high altitude). This review provides an overview of the physiological and morphological aspects of adaptive responses in these environmental stressors at the level of organs, tissues, and cells. Furthermore, adjustments existing in native people living in such extreme conditions on the earth as well as acute adaptive responses in newcomers are discussed. These insights into general adaptability of humans are complemented by outcomes of specific acclimatization/acclimation studies adding important information how to cope appropriately with extreme environmental temperatures and hypoxia.

Neocytolysis is the selective destruction of those erythrocytes that had been formed during stress-erythropoiesis in hypoxia in order to increase the oxygen transport capacity of blood. Neocytolysis likely aims at decreasing this excess amount of erythrocytes and hemoglobin (Hb) when it is not required anymore and to decrease blood viscosity. Neocytolysis seems to occur upon descent from high altitude. Similar processes seem to occur in microgravity, and are also discussed to mediate the replacement of erythrocytes containing fetal hemoglobin (HbF) with those having adult hemoglobin (HbA) after birth. This review will focus on hypoxia at high altitude. Hemoglobin concentration and total hemoglobin in blood increase by 20-50% depending on the altitude (i.e., the degree of hypoxia) and the duration of the sojourn. Upon return to normoxia hemoglobin concentration, hematocrit, and reticulocyte counts decrease faster than expected from inhibition of stress-erythropoiesis and normal erythrocyte destruction rates. In parallel, an increase in haptoglobin, bilirubin, and ferritin is observed, which serve as indirect markers of hemolysis and hemoglobin-breakdown. At the same time markers of progressing erythrocyte senescence appear even on reticulocytes. Unexpectedly, reticulocytes from hypoxic mice show decreased levels of the hypoxia-inducible factor HIF-1α and decreased activity of the BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), which results in elevated mitochondrial activity in these cells. Furthermore, hypoxia increases the expression of miR-21, which inhibits the expression of catalase and thus decreases one of the most important mechanisms protecting against oxygen free radicals in erythrocytes. This unleashes a series of events which likely explain neocytolysis, because upon re-oxygenation systemic and mitochondrial oxygen radical formation increases and causes the selective destruction of those erythrocytes having impaired anti-oxidant capacity.

Berger, Marc Moritz, Franziska Macholz, Peter Schmidt, Sebastian Fried, Tabea Perz, Daniel Dankl, Josef Niebauer, Peter Bärtsch, Heimo Mairbäurl, and Mahdi Sareban. Inhaled budesonide does not affect hypoxic pulmonary vasoconstriction at 4559 meters of altitude. High Alt Med Biol 19:52-59, 2018.-Oral intake of the corticosteroid dexamethasone has been shown to lower pulmonary artery pressure (PAP) and to prevent high-altitude pulmonary edema. This study tested whether inhalation of the corticosteroid budesonide attenuates PAP and right ventricular (RV) function after rapid ascent to 4559 m. In this prospective, randomized, double-blind, and placebo-controlled trial, 50 subjects were randomized into three groups to receive budesonide at 200 or 800 μg twice/day (n = 16 and 17, respectively) or placebo (n = 17). Inhalation was started 1 day before ascending from 1130 to 4559 m within 20 hours. Systolic PAP (SPAP) and RV function were assessed by transthoracic echocardiography at low altitude (423 m) and after 7, 20, 32, and 44 hours at 4559 m. Ascent to high altitude increased SPAP about 1.7-fold (p < 0.001), whereas RV function was preserved. There was no difference in SPAP and RV function between groups at low and high altitude (all p values >0.10). Capillary partial pressure of oxygen (PO 2 ) and carbon dioxide as well as the alveolar to arterial PO 2 difference were decreased at high altitude but not affected by budesonide. Prophylactic inhalation of budesonide does not attenuate high-altitude-induced pulmonary vasoconstriction and RV function after rapid ascent to 4559 m.

Remote ischemic preconditioning (RIPC) has been shown to protect remote organs, such as the brain and the lung, from damage induced by subsequent hypoxia or ischemia. Acute mountain sickness (AMS) is a syndrome of nonspecific neurologic symptoms and in high-altitude pulmonary edema excessive hypoxic pulmonary vasoconstriction (HPV) plays a pivotal role. We hypothesized that RIPC protects the brain from AMS and attenuates the magnitude of HPV after rapid ascent to 3,450 m. Forty nonacclimatized volunteers were randomized into two groups. At low altitude (750 m) the RIPC group ( n = 20) underwent 4 × 5 min of lower-limb ischemia (induced by inflation of bilateral thigh cuffs to 200 mmHg) followed by 5 min of reperfusion. The control group ( n = 20) underwent a sham protocol (4 × 5 min of bilateral thigh cuff inflation to 20 mmHg). Thereafter, participants ascended to 3,450 m by train over 2 h and stayed there for 48 h. AMS was evaluated by the Lake Louise score (LLS) and the AMS-C score. Systolic pulmonary artery pressure (SPAP) was assessed by transthoracic Doppler echocardiography. RIPC had no effect on the overall incidence (RIPC: 35%, control: 35%, P = 1.0) and severity (RIPC vs., Control: P = 0.496 for LLS; P = 0.320 for AMS-C score) of AMS. RIPC also had no significant effect on SPAP [maximum after 10 h at high altitude; RIPC: 33 (SD 8) mmHg; controls: 37 (SD 7) mmHg; P = 0.19]. This study indicates that RIPC, performed immediately before passive ascent to 3,450 m, does not attenuate AMS and the magnitude of high-altitude pulmonary hypertension. NEW & NOTEWORTHY Remote ischemic preconditioning (RIPC) has been reported to improve neurologic and pulmonary outcome following an acute ischemic or hypoxic insult, yet the effect of RIPC for protecting from high-altitude diseases remains to be determined. The present study shows that RIPC, performed immediately before passive ascent to 3,450 m, does not attenuate acute mountain sickness and the degree of high-altitude pulmonary hypertension. Therefore, RIPC cannot be recommended for prevention of high-altitude diseases., (Copyright © 2017 the American Physiological Society.)

The aim of this study was to assess intra- and inter-observer variability of left (LA) and right atrial (RA) strain indices obtained by two-dimensional speckle-tracking echocardiography (2D-STE) in a healthy group of individuals at low-altitude and after rapid ascent to high-altitude in order to provoke altered systemic and pulmonary hemodynamics otherwise seen in various cardiac diseases. Twenty healthy subjects underwent transthoracic echocardiography during a baseline examination at low-altitude (424 m) as well as 7, 20 and 44 h after arrival at high-altitude (4559 m). Atrial strain indices (i.e. reservoir, conduit and contractile strain) were determined off-line by two independent observers. Intra- and inter-observer reproducibility of variables was assessed by intra-class correlation coefficients (ICCs), coefficients of variation and Bland Altman plots. Heart rate, systemic blood pressure and pulmonary artery pressure increased significantly from low-altitude to the first examination at high-altitude. Intra-observer ICCs were ≥0.90 except for RA conduit strain with an ICC of 0.86. The mean intra-observer differences were small and limits of agreement of relative differences were narrow for all atrial strain parameters (<3 and <16%, respectively). Inter-observer ICCs (0.80-0.90), mean biases and limits of agreement (<4 and <20%, respectively) were greater than intra-observer results for all parameters. Intra- and inter-obserer ICCs for all atrial strain variables did not differ between low- and high-altitude. 2D-STE-derived bi-atrial strain indices have excellent intra- and moderate inter-observer reproducibility with no effect of high-altitude-induced hemodynamic changes on reliability results.

Oxygen diffusion across the alveolar wall is compromised by low alveolar oxygen but also by pulmonary edema, and leads to hypoxemia and hypoxic pulmonary vasoconstriction (HPV). To test, whether inhibition of alveolar fluid reabsorption results in an increased pulmonary arterial pressure and whether this effect enhances HPV, we established a model, where anesthetized rats were ventilated with normoxic (21% O 2 ) and hypoxic (13.5% O 2 ) gas received aerosolized amiloride and lipopolisaccharide (LPS) to inhibit alveolar fluid reabsorption. Right ventricular systolic pressure (RVsP) was measured as an indicator of pulmonary arterial pressure. Oxygen pressure (PaO 2 ) and saturation (SaO 2 ) in femoral arterial blood served as indicator of oxygen diffusion across the alveolar wall. Aerosolized amiloride and bacterial LPS decreased PaO 2 and SaO 2 and increased RVsP even when animals were ventilated with normoxic gas. Ventilation with hypoxic gas decreased PaO 2 by 35 mmHg and increased RVsP by 10 mmHg. However, combining hypoxia with amiloride and LPS did not aggravate the decrease in PaO 2 and SaO 2 and had no effect on the increase in RVsP relative to hypoxia alone. There was a direct relation between SaO 2 and PaO 2 and the RVsP under all experimental conditions. Two hours but not 1 h exposure to aerosolized amiloride and LPS in normoxia as well as hypoxia increased the lung wet-to-dry-weight ratio indicating edema formation. Together these findings indicate that inhibition of alveolar reabsorption causes pulmonary edema, impairs oxygen diffusion across the alveolar wall, and leads to an increased pulmonary arterial pressure., (© 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.)

Non-small cell lung cancer (NSCLC) is characterized by early metastasis and has the highest mortality rate among all solid tumors, with the majority of patients diagnosed at an advanced stage where curative therapeutic options are lacking. In this study, we identify a targetable mechanism involving TGFβ elevation that orchestrates tumor progression in this disease. Substantial activation of this pathway was detected in human lung cancer tissues with concomitant downregulation of BAMBI, a negative regulator of the TGFβ signaling pathway. Alterations of epithelial-to-mesenchymal transition (EMT) marker expression were observed in lung cancer samples compared with tumor-free tissues. Distinct alterations in the DNA methylation of the gene regions encoding TGFβ pathway components were detected in NSCLC samples compared with tumor-free lung tissues. In particular, epigenetic silencing of BAMBI was identified as a hallmark of NSCLC. Reconstitution of BAMBI expression in NSCLC cells resulted in a marked reduction of TGFβ-induced EMT, migration, and invasion in vitro, along with reduced tumor burden and tumor growth in vivo In conclusion, our results demonstrate how BAMBI downregulation drives the invasiveness of NSCLC, highlighting TGFβ signaling as a candidate therapeutic target in this setting. Cancer Res; 76(13); 3785-801. ©2016 AACR., (©2016 American Association for Cancer Research.)

The high-mobility group box 1 (HMGB1) protein has a central role in immunological antitumour defense. Here we show that natural killer cell-derived HMGB1 directly eliminates cancer cells by triggering metabolic cell death. HMGB1 allosterically inhibits the tetrameric pyruvate kinase isoform M2, thus blocking glucose-driven aerobic respiration. This results in a rapid metabolic shift forcing cells to rely solely on glycolysis for the maintenance of energy production. Cancer cells can acquire resistance to HMGB1 by increasing glycolysis using the dimeric form of PKM2, and employing glutaminolysis. Consistently, we observe an increase in the expression of a key enzyme of glutaminolysis, malic enzyme 1, in advanced colon cancer. Moreover, pharmaceutical inhibition of glutaminolysis sensitizes tumour cells to HMGB1 providing a basis for a therapeutic strategy for treating cancer.

Acute respiratory distress syndrome (ARDS) is clinical syndrome characterized by decreased lung fluid reabsorption, causing alveolar edema. Defective alveolar ion transport undertaken in part by the Na(+)/K(+)-ATPase underlies this compromised fluid balance, although the molecular mechanisms at play are not understood. We describe here increased expression of FXYD1, FXYD3 and FXYD5, three regulatory subunits of the Na(+)/K(+)-ATPase, in the lungs of ARDS patients. Transforming growth factor (TGF)-β, a pathogenic mediator of ARDS, drove increased FXYD1 expression in A549 human lung alveolar epithelial cells, suggesting that pathogenic TGF-β signaling altered Na(+)/K(+)-ATPase activity in affected lungs. Lentivirus-mediated delivery of FXYD1 and FXYD3 allowed for overexpression of both regulatory subunits in polarized H441 cell monolayers on an air/liquid interface. FXYD1 but not FXYD3 overexpression inhibited amphotericin B-sensitive equivalent short-circuit current in Ussing chamber studies. Thus, we speculate that FXYD1 overexpression in ARDS patient lungs may limit Na(+)/K(+)-ATPase activity, and contribute to edema persistence., (Copyright © 2015 Elsevier B.V. All rights reserved.)

An exaggerated increase in pulmonary arterial systolic pressure (PAsP) is a highlight of high altitude pulmonary edema (HAPE). However, the incidence of HAPE at 4559 m was much lower in altitude-naïve individuals with exaggerated pulmonary vasoconstriction (HPV) in normobaric hypoxia than in known HAPE-susceptibles, indicating that elevated PAsP alone is insufficient to induce HAPE. A decreased nasal potential difference (NPD) has been found in HAPE-susceptibles, where, based on animal models, NPD serves as surrogate of alveolar epithelial ion transport. We hypothesize that those HAPE-resistant individuals with high HPV may be protected by elevated alveolar Na and fluid reabsorption, which might be detected as increased NPD. To test this hypothesis, we measured NPD in normoxia of subjects who were phenotyped in previous studies as high altitude tolerant (controls), known HAPE-susceptibles with high HPV (HP+HAPE), as well as individuals with high HPV but without HAPE (HP-no-HAPE) at 4559 m. NPD and amiloride-sensitive NPD were lower in HP+HAPE than in controls, whereas HP-no-HAPE were not different from either group. There were no differences in Cl-transport between groups. Our results show low nasal ion transport in HAPE but higher transport in those individuals with the highest HPV but without HAPE. This indicates that in some individuals with high PAsP at high altitude high alveolar fluid reabsorption might protect them from HAPE.

Preconditioning refers to exposure to brief episodes of potentially adverse stimuli and protects against injury during subsequent exposures. This was first described in the heart, where episodes of ischemia/reperfusion render the myocardium resistant to subsequent ischemic injury, which is likely caused by reactive oxygen species (ROS) and proinflammatory processes. Protection of the heart was also found when preconditioning was performed in an organ different from the target, which is called remote ischemic preconditioning (RIPC). The mechanisms causing protection seem to include stimulation of nitric oxide (NO) synthase, increase in antioxidant enzymes, and downregulation of proinflammatory cytokines. These pathways are also thought to play a role in high-altitude diseases: high-altitude pulmonary edema (HAPE) is associated with decreased bioavailability of NO and increased generation of ROS, whereas mechanisms causing acute mountain sickness (AMS) and high-altitude cerebral edema (HACE) seem to involve cytotoxic effects by ROS and inflammation. Based on these apparent similarities between ischemic damage and AMS, HACE, and HAPE, it is reasonable to assume that RIPC might be protective and improve altitude tolerance. In studies addressing high-altitude/hypoxia tolerance, RIPC has been shown to decrease pulmonary arterial systolic pressure in normobaric hypoxia (13% O2) and at high altitude (4,342 m). Our own results indicate that RIPC transiently decreases the severity of AMS at 12% O2. Thus preliminary studies show some benefit, but clearly, further experiments to establish the efficacy and potential mechanism of RIPC are needed., (Copyright © 2015 the American Physiological Society.)

Acute mountain sickness (AMS) is a neurological disorder occurring when ascending too fast, too high. Remote ischemic preconditioning (RIPC) is a noninvasive intervention protecting remote organs from subsequent hypoxic damage. We hypothesized that RIPC protects against AMS and that this effect is related to reduced oxidative stress. Fourteen subjects were exposed to 18 hours of normoxia (21% oxygen) and 18 h of normobaric hypoxia (12% oxygen, equivalent to 4500 m) on different days in a blinded, randomized order. RIPC consisted of four cycles of lower limb ischemia (5 min) and 5 min of reperfusion, and was performed immediately before the study room was entered. A control group was exposed to hypoxia (12% oxygen, n = 14) without RIPC. AMS was evaluated by the Lake Louise score (LLS) and the AMS-C score of the Environmental Symptom Questionnaire. Plasma concentrations of ascorbate radicals, oxidized sulfhydryl (SH) groups, and electron paramagnetic resonance (EPR) signal intensity were measured as biomarkers of oxidative stress. RIPC reduced AMS scores (LLS: 1.9 ± 0.4 vs. 3.2 ± 0.5; AMS-C score: 0.4 ± 0.1 vs. 0.8 ± 0.2), ascorbate radicals (27 ± 7 vs. 65 ± 18 nmol/L), oxidized SH groups (3.9 ± 1.4 vs. 14.3 ± 4.6 μmol/L), and EPR signal intensity (0.6 ± 0.2 vs. 1.5 ± 0.4 × 10(6)) after 5 h in hypoxia (all P < 0.05). After 18 hours in hypoxia there was no difference in AMS and oxidative stress between RIPC and control. AMS and plasma markers of oxidative stress did not correlate. This study demonstrates that RIPC transiently reduces symptoms of AMS and that this effect is not associated with reduced plasma levels of reactive oxygen species., (© 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.)

Low iron availability enhances hypoxic pulmonary vasoconstriction (HPV). Considering that reduced serum iron is caused by increased erythropoiesis, insufficient reabsorption, or elevated hepcidin levels, one might speculate that exaggerated HPV in high-altitude pulmonary edema (HAPE) is related to low serum iron. To test this notion we measured serum iron and hepcidin in blood samples obtained in previously published studies at low altitude and during 2 days at 4,559 m (HA1, HA2) from controls, individuals with HAPE, and HAPE-susceptible individuals where prophylactic dexamethasone and tadalafil prevented HAPE. As reported, at 4,559 m pulmonary arterial pressure was increased in healthy volunteers but reached higher levels in HAPE. Serum iron levels were reduced in all groups at HA2. Hepcidin levels were reduced in all groups at HA1 and HA2 except in HAPE, where hepcidin was decreased at HA1 but unexpectedly high at HA2. Elevated hepcidin in HAPE correlated with increased IL-6 at HA2, suggesting that an inflammatory response related to HAPE contributes to increased hepcidin. Likewise, platelet-derived growth factor, a regulator of hepcidin, was increased at HA1 and HA2 in controls but not in HAPE, suggesting that hypoxia-controlled factors that regulate serum iron are inappropriately expressed in HAPE. In summary, we found that HAPE is associated with inappropriate expression of hepcidin without inducing expected changes in serum iron within 2 days at HA, likely due to too short time. Although hepcidin expression is uncoupled from serum iron availability and hypoxia in individuals developing HAPE, our findings indicate that serum iron is not related with exaggerated HPV., (Copyright © 2015 the American Physiological Society.)

We previously demonstrated that intratracheally administered S-ketamine inhibits alveolar fluid clearance (AFC), whereas an intravenous (i.v.) bolus injection had no effect. The aim of the present study was to characterize whether continuous i.v. infusion of S-ketamine, yielding clinically relevant plasma concentrations, inhibits AFC and whether its effect is enhanced in acute lung injury (ALI) which might favor the appearance of i.v. S-ketamine at the alveolar surface. AFC was measured in fluid-instilled rat lungs. S-ketamine was administered i.v. over 6 h (loading dose: 20 mg/kg, followed by 20 mg/kg/h), or intratracheally by addition to the instillate (75 µg/ml). ALI was induced by i.v. lipopolysaccharide (LPS; 7 mg/kg). Interleukin (IL)-6 and cytokine-induced neutrophil chemoattractant (CINC)-3 were measured by ELISA in plasma and bronchoalveolar lavage fluid. Isolated rat alveolar type-II cells were exposed to S-ketamine (75 µg/ml) and/or LPS (1 mg/ml) for 6 h, and transepithelial ion transport was measured as short circuit current (ISC). AFC was 27±5% (mean±SD) over 60 min in control rats and was unaffected by i.v. S-ketamine. Tracheal S-ketamine reduced AFC to 18±9%. In LPS-treated rats, AFC decreased to 16±6%. This effect was not enhanced by i.v. S-ketamine. LPS increased IL-6 and CINC-3 in plasma and bronchoalveolar lavage fluid. In alveolar type-II cells, S-ketamine reduced ISC by 37% via a decrease in amiloride-inhibitable sodium transport. Continuous administration of i.v. S-ketamine does not affect rat AFC even in endotoxin-induced ALI. Tracheal application with direct exposure of alveolar epithelial cells to S-ketamine decreases AFC by inhibition of amiloride-inhibitable sodium transport.