Hypoxic preacclimatization combining intermittent hypoxia exposure with physical exercise significantly promotes the tolerance to acute hypoxia.

Background: Both hypoxia exposure and physical exercise before ascending have been proved to promote high altitude acclimatization, whether the combination of these two methods can bring about a better effect remains uncertain. Therefore, we designed this study to evaluate the effect of hypoxic preacclimatization combining intermittent hypoxia exposure (IHE) and physical exercise on the tolerance to acute hypoxia and screen the optimal preacclimatization scheme among the lowlanders. Methods: A total of 120 Han Chinese young men were enrolled and randomly assigned into four groups, including the control group and three experimental groups with hypoxic preacclimatization of 5-day rest, 5-day exercise, and 3-day exercise in a hypobaric chamber, respectively. Main physical parameters for hypoxia acclimatization, AMS incidence, physical and mental capacity were measured for each participant in the hypobaric chamber simulated to the altitude of 4500 m in the effect evaluation stage. The effect was compared between different schemes. Results: During the effect evaluation stage, SpO2 of the 5-day rest group and 5-day exercise group was significantly higher than that of the control group (p = 0.001 and p = 0.006, respectively). The participants with 5-day rest had significantly lower HR than the controls (p = 0.018). No significant differences of AMS incidence were found among the four groups, while the proportion of AMS headache symptom (moderate and severe vs. mild) was significantly lower in the 3-day exercise group than that in the control group (p = 0.002). The 5-day exercise group had significantly higher VO2max, than the other three groups (p = 0.033, p < 0.001, and p = 0.023, respectively). The 5-day exercise group also had significantly higher digital symbol and pursuit aiming test scores, while shorter color selection reaction time than the control group (p = 0.005, p = 0.005, and p = 0.004, respectively). Conclusion: Hypoxic preacclimatization combining IHE with physical exercise appears to be efficient in promoting the tolerance to acute hypoxia. Hypoxia duration and physical exercise of moderate intensity are helpful for improvement of SpO2 and HR, relief of AMS headache symptoms, and enhancement of mental and physical operation capacity.

Remote ischemic preconditioning improves spatial memory and sleep of young males during acute high-altitude exposure.

OBJECTIVE: The high-altitude hypoxia environment will cause poor acclimatization in a portion of the population. Remote ischemic preconditioning（RIPC）has been demonstrated to prevent cardiovascular and cerebrovascular diseases under ischemic or hypoxic conditions. However, its role in improving acclimatization and preventing acute mountain sickness (AMS) at high altitude has been undetermined. This study aims to estimate the effect of RIPC on acclimatization of individuals exposed to high altitude. METHODS: The project was designed as a randomized controlled trial with 82 healthy young males, who received RIPC training once a day for 7 consecutive days. Then they were transported by aircraft to a high altitude (3680 m) and examined for 6 days. Lake Louise Score(LLS) of AMS, physiological index, self-reported sleep pattern, and Pittsburgh Sleep Quality Index（PSQI）score were applied to assess the acclimatization to the high altitude. Five neurobehavioral tests were conducted to assess cognitive function. RESULTS: The result showed that the RIPC group had a significantly lower AMSscore than the control group (2.43 ± 1.58 vs 3.29 ± 2.03, respectively; adjusted mean difference-0.84, 95% confidence interval-1.61 to -0.06, P = 0.036). and there was no significant difference in AMS incidence between the two groups (25.0% vs 28.57%, P = 0.555). The RIPC group performed better than the control group in spatial memory span score (11[9-12] vs 10[7.5-11], P=0.025) and the passing digit (7[6-7.5] vs 6[5-7], P= 0.001). Spatial memory was significantly higher in the high-altitude RIPC group than in the low-altitude RIPC group (P＜0.01). And the RIPC group obtained significantly lower self-reported sleep quality score (P = 0.024) and PSQI score (P = 0.031). CONCLUSIONS: The RIPC treatment improved spatial memory and sleep quality in subjects exposed to acute hypoxic exposure and this may lead to improved performance at high altitude.

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

Remote ischemic preconditioning (RIPC) may improve exercise performance. However, the influence of RIPC on aerobic performance and underlying physiological mechanisms during hypobaric hypoxia (HH) exposure remains relatively uncertain. Here, we systematically evaluated the potential performance benefits and underlying mechanisms of RIPC during HH exposure. Seventy-nine healthy participants were randomly assigned to receive sham intervention or RIPC (4 × 5 min occlusion 180 mm Hg/reperfusion 0 mm Hg, bilaterally on the upper arms) for 8 consecutive days in phases 1 (24 participants) and phase 2 (55 participants). In the phases 1, we measured the change in maximal oxygen uptake capacity (VO2max) and muscle oxygenation (SmO2) on the leg during a graded exercise test. We also measured regional cerebral oxygenation (rSO2) on the forehead. These measures and physiological variables, such as cardiovascular hemodynamic parameters and heart rate variability index, were used to evaluate the intervention effect of RIPC on the changes in bodily functions caused by HH exposure. In the phase 2, plasma protein mass spectrometry was then performed after RIPC intervention, and the results were further evaluated using ELISA tests to assess possible mechanisms. The results suggested that RIPC intervention improved VO2max (11.29%) and accelerated both the maximum (18.13%) and minimum (53%) values of SmO2 and rSO2 (6.88%) compared to sham intervention in hypobaric hypoxia exposure. Cardiovascular hemodynamic parameters (SV, SVRI, PPV% and SpMet%) and the heart rate variability index (Mean RR, Mean HR, RMSSD, pNN50, Lfnu, Hfnu, SD1, SD2/SD1, ApEn, SampEn, DFA1and DFA2) were evaluated. Protein sequence analysis showed 42 unregulated and six downregulated proteins in the plasma of the RIPC group compared to the sham group after HH exposure. Three proteins, thymosin ß4 (Tß4), heat shock protein-70 (HSP70), and heat shock protein-90 (HSP90), were significantly altered in the plasma of the RIPC group before and after HH exposure. Our data demonstrated that in acute HH exposure, RIPC mitigates the decline in VO2max and regional oxygenation, as well as physiological variables, such as cardiovascular hemodynamic parameters and the heart rate variability index, by influencing plasma Tß4, HSP70, and HSP90. These data suggest that RIPC may be beneficial for acute HH exposure.

Short-Term High-Altitude Exposure (3600 m) Alters the Type Distribution of Sperm Deformity.

Background: The effect of short-term exposure to high altitudes below 4000 m on the distribution of sperm abnormality is a matter of concern with regard to the ability for fertilization, and rarely reported. Materials and Methods: The survey subjects, who had not visited the high plateau previously, were divided into three groups: two high-plateau groups and the low-altitude control group. In the high-plateau groups, healthy young men had been living in Lhasa City, Tibet (3600 m), for 1 or 3 months. Similar subjects in Chongqing City (400 m) were used as the control group. Semen was collected, and semen volume, pH, and sperm concentration were analyzed. After observing sperm morphology by light microscopy, we measured the percentage of sperm abnormality and statistically analyzed its type distribution. Results: Sperm concentration was decreased significantly after 3 months of high-altitude exposure (p < 0.01). The total sperm malformation rate did not change, but the head malformation rate was increased (p < 0.05). In addition, there were changes in the distribution of sperm malformation. The occurrence and frequency of sperm with excessive head size, neck crimp, and tailless were increased significantly (p < 0.01, p < 0.01, and p < 0.05, respectively) at 3 months. Conclusion: Our study demonstrates that short-term high-altitude exposure of >1 month at 3600 m increases the distribution of sperm deformities.

Excessive Iron Availability Caused by Disorders of Interleukin-10 and Interleukin-22 Contributes to High Altitude Polycythemia.

Background: Because the pathogenesis of high altitude polycythemia (HAPC) is unclear, the aim of the present study was to explore whether abnormal iron metabolism is involved in the pathogenesis of HAPC and the possible cause. Methods: We examined the serum levels of iron, total iron binding capacity, soluble transferrin receptor (sTfR), ferritin, and hepcidin as well as erythropoietin (EPO) and inflammation-related cytokines in 20 healthy volunteers at sea level, 36 healthy high-altitude migrants, and 33 patients with HAPC. Mice that were exposed to a simulated hypoxic environment at an altitude of 5,000 m for 4 weeks received exogenous iron or intervention on cytokines, and the iron-related and hematological indices of peripheral blood and bone marrow were detected. The in vitro effects of some cytokines on hematopoietic cells were also observed. Results: Iron mobilization and utilization were enhanced in people who had lived at high altitudes for a long time. Notably, both the iron storage in ferritin and the available iron in the blood were elevated in patients with HAPC compared with the healthy high-altitude migrants. The correlation analysis indicated that the decreased hepcidin may have contributed to enhanced iron availability in HAPC, and decreased interleukin (IL)-10 and IL-22 were significantly associated with decreased hepcidin. The results of the animal experiments confirmed that a certain degree of iron redundancy may promote bone marrow erythropoiesis and peripheral red blood cell production in hypoxic mice and that decreased IL-10 and IL-22 stimulated iron mobilization during hypoxia by affecting hepcidin expression. Conclusion: These data demonstrated, for the first time, that an excess of obtainable iron caused by disordered IL-10 and IL-22 was involved in the pathogenesis of some HAPC patients. The potential benefits of iron removal and immunoregulation for the prevention and treatment of HAPC deserve further research.

Th2 lymphocytes migrating to the bone marrow under high-altitude hypoxia promote erythropoiesis via activin A and interleukin-9.

The mechanism of accelerated erythropoiesis under the hypoxic conditions of high altitude (HA) remains largely obscure. Here, we investigated the potential role of bone marrow (BM) T cells in the increased production of erythrocytes at HA. We found that mice exposed to a simulated altitude of 6,000 m for 1-3 weeks exhibited a significant expansion of BM CD4+ cells, mainly caused by increasing T helper 2 (Th2) cells. Using a coculture model of BM T cells and hematopoietic stem/progenitor cells, we observed that BM CD4+ cells from hypoxic mice induced erythroid output more easily, in agreement with the erythroid-enhancing effect observed for Th2-condition-cultured BM CD4+ cells. It was further demonstrated that elevated secretion of activin A and interleukin-9 by BM Th2 cells of hypoxic mice promoted erythroid differentiation of hematopoietic stem/progenitor cells and the growth of erythroblasts, respectively. Our study also provided evidence that the CXCL12-CXCR4 interaction played an important role in Th2 cell trafficking to the BM under HA conditions. These results collectively suggest that Th2 cells migrating to the BM during HA exposure have a regulatory role in erythropoiesis, which provides new insight into the mechanism of high altitude polycythemia.

The effects of short-term and long-term exposure to a high altitude hypoxic environment on neurobehavioral function.

AIMS: Examined the change in neurobehavioral function of individuals acclimated to high altitudes and those native to high altitudes. METHODS: A neurobehavioral core test battery approved by the WHO (WHO-NCTB) was used to evaluate the effects of high altitude hypoxia on neurobehavioral function. The WHO-NCTB is composed of seven individual tests: a mood state profile, simple reaction time test, digit span test, Santa Ana manual dexterity test, digit symbol test, Benton visual retention test, and pursuit aiming test. RESULTS: The values from the Santa Ana manual dexterity test, digit symbol test, and pursuit aiming test from sea-level subjects acclimated for 5 days at 3700 m were significantly decreased when compared with the same subjects at sea level. The values from the digit span, Santa Ana manual dexterity, digit symbol, Benton visual retention and pursuit aiming tests in subjects native to high altitudes of 3700, 4500, and 5100 m were significantly decreased when compared with subjects at sea level and compared with sea-level subjects acclimated for 5 days at 3700 m. CONCLUSIONS: These results demonstrate that high altitude hypoxia induces damage to neurobehavioral functions, and the long-term deficit in neurobehavioral function was more severe than the short-term changes.

Anti-fatigue effects of Panax notoginseng in simulation plateau-condition mice.

BACKGROUND: Panax notoginseng (PN) is one of the most commonly used Chinese herbal drugs. Panax notoginseng saponins (PNS) is the main effective components of PN. However, the anti-fatigue effect of PNS in plateau-condition is unknown. OBJECTIVE: Explore the anti-fatigue effects of PNS in mice living under simulation plateau-condition. MATERIALS AND METHODS: Hundred male Kunming mice were randomly divided into five groups (n=20): one normoxia control group (NCG), one hypoxia control group (HCG), and three PNS groups in low dosage (0.42 g/kg), mid dosage (1.11 g/kg), and high dosage (11.53 g/kg). HCG and PNS groups were fed at a simulated elevation of 5 km. NCG and HCG were intragastric administrated with distilled water. After continuous administration for 10 days, the exhaustive swimming time, glycogen contents in liver, blood lactic acid (BLA), and blood glucose were determined. RESULTS: Exposure of the mice to simulation plateau-condition with 5 km altitude for 10 days caused significant decrease of exercise tolerance compared to normoxia environment. The swimming time and glycogen contents in liver were significantly increased at all tested concentration (0.42, 1.11, and 11.53 g/kg). The area under the BLA curve was significantly decreased at the concentration of 0.42 g/ kg. The blood glucose of resting and 0 minutes after swimming were significantly increased by 29.31% and 15.51% (P<0.05) at a concentration of 11.53 g/kg compared to their own control groups, respectively. CONCLUSION: These results indicate that PNS could postpone the appearance of fatigue and accelerate the restoration of fatigue in plateau environment, especially in low dosage (0.42 g/kg) case.

Regulation of bone marrow hematopoietic stem cell is involved in high-altitude erythrocytosis.

OBJECTIVE: Hypoxia at high altitudes can lead to increased production of red blood cells through the hormone erythropoietin (EPO). In this study, we observed how the EPO-unresponsive hematopoietic stem cell (HSC) compartment responds to high-altitude hypoxic environments and contributes to erythropoiesis. MATERIALS AND METHODS: Using a mouse model at simulated high altitude, the bone marrow (BM) and spleen lineage marker(-)Sca-1(+)c-Kit(+) (LSK) HSC compartment were observed in detail. Normal LSK cells were then cultured under different conditions (varying EPO levels, oxygen concentrations, and BM supernatants) to investigate the causes of the HSC responses. RESULTS: Hypoxic mice exhibited a marked expansion in BM and spleen LSK compartments, which were associated with enhanced proliferation. BM HSCs seemed to play a more important role in erythropoiesis at high altitude than spleen HSCs. There was also a lineage fate change of BM HSCs in hypoxic mice that was manifested in increased megakaryocyte-erythrocyte progenitors and periodically reduced granulocyte-macrophage progenitors in the BM. The LSK cells in hypoxic mice displayed upregulated erythroid-specific GATA-1 and downregulated granulocyte-macrophage-specific PU.1 messenger RNA expression, as well as the capacity to differentiate into more erythroid precursors after culture. BM culture supernatant from hypoxic mice (but not elevated EPO or varying O(2) tension) could induce expansion and erythroid-priority differentiation of the HSC population, a phenomenon partially caused by increasing interleukin-3 and interleukin-6 secretion in the BM. CONCLUSIONS: The present study suggests a new EPO-independent HSC mechanism of high-altitude erythrocytosis.

Exposure to di(n-butyl)phthalate and benzo(a)pyrene alters IL-1ß secretion and subset expression of testicular macrophages, resulting in decreased testosterone production in rats.

Di(n-butyl)phthalate (DBP) and benzo(a)pyrene (BaP) are environmental endocrine disruptors that are potentially hazardous to humans. These chemicals affect testicular macrophage immuno-endocrine function and testosterone production. However, the underlying mechanisms for these effects are not fully understood. It is well known that interleukin-1 beta (IL-1ß), which is secreted by testicular macrophages, plays a trigger role in regulating Leydig cell steroidogenesis. The purpose of this study was to reveal the effects of co-exposure to DBP and BaP on testicular macrophage subset expression, IL-1ß secretion and testosterone production. Adult male Sprague-Dawley rats were randomly divided into seven groups; two groups received DBP plus BaP (DBP+BaP: 50+1 or 250+5mg/kg/day) four groups received DBP or BaP alone (DBP: 50 or 250 mg/kg/day; BaP: 1 or 5mg/kg/day), and one group received vehicle alone (control). After co-exposure for 90 days, the relative expression of macrophage subsets and their functions changed. ED2(+) testicular macrophages (reactive with a differentiation-related antigen present on the resident macrophages) were activated and IL-1ß secretion was enhanced. DBP and BaP acted additively, as demonstrated by greater IL-1ß secretion relative to each compound alone. These observations suggest that exposure to DBP plus BaP exerted greater suppression on testosterone production compared with each compound alone. The altered balance in the subsets of testicular macrophages and the enhanced ability of resident testicular macrophages to secrete IL-1ß, resulted in enhanced production of IL-1ß as a potent steroidogenesis repressor. This may represent an important mechanism by which DBP and BaP repress steroidogenesis.