RESUMEN
High-altitude hypoxia exposure can lead to phospholipase D-mediated lipid metabolism disorder in spleen tissues and induce ferroptosis. Nonetheless, the key genes underlying hypoxia-induced splenic phospholipase D and the ferroptosis pathway remain unclear. This study aimed to establish a hypoxia animal model. Combined transcriptomic and proteomic analyses showed that 95 predicted target genes (proteins) were significantly differentially expressed under hypoxic conditions. Key genes in phospholipase D and ferroptosis pathways under hypoxic exposure were identified by combining Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis techniques. Gene set enrichment analysis (GSEA) showed that the differential gene sets of the phospholipase D and ferroptosis signaling pathways were upregulated in the high-altitude hypoxia group. The genes in the phospholipase D signalling pathway were verified, and the expression levels of KIT and DGKG were upregulated in spleen tissues under hypoxic exposure. Subsequently, the mRNA and protein expression levels of genes from the exogenous pathway such as TFRC, SLC40A1, SLC7A11, TRP53, and FTH1 and those from the endogenous pathway such as GPX4, HMOX1, and ALOX15 differentials in the ferroptosis signalling pathway were verified, and the results indicated significant differential expression. In summary, exposure to high-altitude hypoxia mediated phospholipid metabolism disturbance through the phospholipase D signalling pathway and further induced ferroptosis, leading to splenic injury.
Asunto(s)
Mal de Altura , Ferroptosis , Fosfolipasa D , Animales , Ratones , Mal de Altura/genética , Mal de Altura/metabolismo , Hipoxia , Fosfolipasa D/metabolismo , Proteómica , Transducción de Señal , Bazo/metabolismo , Bazo/patologíaRESUMEN
Exposure to high altitudes generates a decrease in the partial pressure of oxygen, triggering a hypobaric hypoxic condition. This condition produces pathophysiologic alterations in an organism. In the lung, one of the principal responses to hypoxia is the development of hypoxic pulmonary vasoconstriction (HPV), which improves gas exchange. However, when HPV is exacerbated, it induces high-altitude pulmonary hypertension (HAPH). Another important illness in hypobaric hypoxia is high-altitude pulmonary edema (HAPE), which occurs under acute exposure. Several studies have shown that inflammatory processes are activated in high-altitude illnesses, highlighting the importance of the crosstalk between hypoxia and inflammation. The aim of this review is to determine the inflammatory pathways involved in hypobaric hypoxia, to investigate the key role of inflammation in lung pathologies, such as HAPH and HAPE, and to summarize different anti-inflammatory treatment approaches for these high-altitude illnesses. In conclusion, both HAPE and HAPH show an increase in inflammatory cell infiltration (macrophages and neutrophils), cytokine levels (IL-6, TNF-α and IL-1ß), chemokine levels (MCP-1), and cell adhesion molecule levels (ICAM-1 and VCAM-1), and anti-inflammatory treatments (decreasing all inflammatory components mentioned above) seem to be promising mitigation strategies for treating lung pathologies associated with high-altitude exposure.
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Mal de Altura , Hipertensión Pulmonar , Infecciones por Papillomavirus , Edema Pulmonar , Humanos , Hipertensión Pulmonar/metabolismo , Molécula 1 de Adhesión Intercelular , Altitud , Edema Pulmonar/patología , Molécula 1 de Adhesión Celular Vascular , Factor de Necrosis Tumoral alfa , Interleucina-6 , Infecciones por Papillomavirus/complicaciones , Mal de Altura/metabolismo , Hipoxia/metabolismo , Edema/complicaciones , Citocinas , Inflamación/complicaciones , OxígenoRESUMEN
BACKGROUND: Critical hypoxia in this COVID-19 pandemic results in high mortality and economic loss worldwide. Initially, this disease' pathophysiology was poorly understood and interpreted as a SARS (Severe Acute Respiratory Syndrome) pneumonia. The severe atypical lung CAT scan images alerted all countries, including the poorest, to purchase lacking sophisticated ventilators. However, up to 88% of the patients on ventilators lost their lives. It was suggested that COVID-19 could be similar to a High-Altitude Pulmonary Edema (HAPE). New observations and pathological findings are gradually clarifying the disease. METHODS: As high-altitude medicine and hypoxia physiology specialists working and living in the highlands for over 50 years, we perform a perspective analysis of hypoxic diseases treated at high altitudes and compare them to Covid-19. Oxygen transport physiology, SARS-Cov-2 characteristics, and its transmission, lung imaging in COVID-19, and HAPE, as well as the causes of clinical signs and symptoms, are discussed. RESULTS: High-altitude oxygen transport physiology has been systematically ignored. COVID-19 signs and symptoms indicate a progressive and irreversible failure in the oxygen transport system, secondary to pneumolysis produced by SARS-Cov-2's alveolar-capillary membrane "attack". HAPE's pulmonary compromise is treatable and reversible. COVID-19 is associated with several diseases, with different individual outcomes, in different countries, and at different altitudes. CONCLUSIONS: The pathophysiology of High-altitude illnesses can help explain COVID-19 pathophysiology, severity, and management. Early diagnosis and use of EPO, acetylsalicylic-acid, and other anti-inflammatories, oxygen therapy, antitussives, antibiotics, and the use of Earth open-circuit- astronaut-resembling suits to return to daily activities, should all be considered. Ventilator use can be counterproductive. Immunity development is the only feasible long-term survival tool.
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COVID-19/metabolismo , COVID-19/fisiopatología , Oxígeno/metabolismo , Mal de Altura/diagnóstico , Mal de Altura/metabolismo , Mal de Altura/fisiopatología , COVID-19/diagnóstico , COVID-19/terapia , Diagnóstico Diferencial , Humanos , Hipertensión Pulmonar/diagnóstico , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/fisiopatología , Ventiladores MecánicosRESUMEN
Human high-altitude (HA) adaptation or mal-adaptation is explored to understand the physiology, pathophysiology, and molecular mechanisms that underlie long-term exposure to hypoxia. Here, we report the results of an analysis of the largest whole-genome-sequencing of Chronic Mountain Sickness (CMS) and nonCMS individuals, identified candidate genes and functionally validated these candidates in a genetic model system (Drosophila). We used PreCIOSS algorithm that uses Haplotype Allele Frequency score to separate haplotypes carrying the favored allele from the noncarriers and accordingly, prioritize genes associated with the CMS or nonCMS phenotype. Haplotypes in eleven candidate regions, with SNPs mostly in nonexonic regions, were significantly different between CMS and nonCMS subjects. Closer examination of individual genes in these regions revealed the involvement of previously identified candidates (e.g., SENP1) and also unreported ones SGK3, COPS5, PRDM1, and IFT122 in CMS. Remarkably, in addition to genes like SENP1, SGK3, and COPS5 which are HIF-dependent, our study reveals for the first time HIF-independent gene PRDM1, indicating an involvement of wider, nonHIF pathways in HA adaptation. Finally, we observed that down-regulating orthologs of these genes in Drosophila significantly enhanced their hypoxia tolerance. Taken together, the PreCIOSS algorithm, applied on a large number of genomes, identifies the involvement of both new and previously reported genes in selection sweeps, highlighting the involvement of multiple hypoxia response systems. Since the overwhelming majority of SNPs are in nonexonic (and possibly regulatory) regions, we speculate that adaptation to HA necessitates greater genetic flexibility allowing for transcript variability in response to graded levels of hypoxia.
Asunto(s)
Aclimatación/genética , Mal de Altura/genética , Adaptación Fisiológica/genética , Adulto , Alelos , Altitud , Mal de Altura/metabolismo , Mal de Altura/fisiopatología , Animales , Enfermedad Crónica , Drosophila/genética , Evolución Molecular , Frecuencia de los Genes/genética , Haplotipos/genética , Humanos , Hipoxia/genética , Hipoxia/fisiopatología , Masculino , Perú , Polimorfismo de Nucleótido Simple/genética , Factor 1 de Unión al Dominio 1 de Regulación Positiva/genética , Factor 1 de Unión al Dominio 1 de Regulación Positiva/metabolismo , Secuenciación Completa del Genoma/métodosRESUMEN
Excessive erythrocytosis (EE) is the main sign of Chronic Mountain Sickness (CMS), a highly prevalent syndrome in Andean highlanders. Low pulse O2 saturation (SpO2) during sleep and serum androgens have been suggested to contribute to EE in CMS patients. However, whether these factors have a significant impact on the erythropoietin (Epo) system leading to EE is still unclear. We have recently shown that morning soluble Epo receptor (sEpoR), an endogenous Epo antagonist, is decreased in CMS patients suggesting increased Epo availability (increased Epo/sEpoR). The present study aimed to characterize the nocturnal concentration profile of sEpoR and Epo and their relationship with SpO2, Hct, and serum testosterone in healthy highlanders (HH) and CMS patients. Epo and sEpoR concentrations were evaluated every 4 h (6 PM to 6 AM) and nighttime SpO2 was continuously monitored (10 PM to 6 AM) in 39 male participants (CMS, n = 23; HH, n = 16) aged 21-65 yr from Cerro de Pasco, Peru (4,340 m). CMS patients showed higher serum Epo concentrations throughout the night and lower sEpoR from 10 PM to 6 AM. Consequently, Epo/sEpoR was significantly higher in the CMS group at every time point. Mean sleep-time SpO2 was lower in CMS patients compared with HH, while the percentage of sleep time spent with SpO2 < 80% was higher. Multiple-regression analysis showed mean sleep-time SpO2 and Epo/sEpoR as significant predictors of hematocrit corrected for potential confounders (age, body mass index, and testosterone). Testosterone levels were associated neither with Hct nor with erythropoietic factors. In conclusion, our results show sustained erythropoietic stimulus driven by the Epo system in CMS patients, further enhanced by a continuous exposure to accentuated nocturnal hypoxemia.
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Mal de Altura/sangre , Mal de Altura/metabolismo , Receptores de Eritropoyetina/sangre , Receptores de Eritropoyetina/metabolismo , Sueño/fisiología , Adulto , Anciano , Altitud , Mal de Altura/fisiopatología , Andrógenos/sangre , Enfermedad Crónica , Hematócrito/métodos , Humanos , Hipoxia/sangre , Hipoxia/metabolismo , Hipoxia/fisiopatología , Masculino , Persona de Mediana Edad , Oxígeno/metabolismo , Perú , Policitemia/metabolismo , Policitemia/fisiopatología , Testosterona/sangre , Adulto JovenRESUMEN
Kiyamu, Melisa, Fabiola León-Velarde, María Rivera-Chira, Gianpietro Elías, and Tom D. Brutsaert. Developmental effects determine submaximal arterial oxygen saturation in Peruvian Quechua. High Alt Med Biol 16, 138-146, 2015.--Andean high altitude natives show higher arterial oxygen saturation (Sao(2)) during exercise in hypoxia, compared to acclimatized sojourners. In order to evaluate the effects of life-long exposure to high altitude on Sao(2), we studied two groups of well-matched, self-identified Peruvian Quechua natives who differed in their developmental exposure to hypoxia before and after a 2-month training period. Male and female volunteers (18-35 years) were recruited in Lima, Peru (150 m). The two groups were: a) Individuals who were born and raised at sea-level (BSL, n=34) and b) Individuals who were born and raised at high altitude (BHA, n=32), but who migrated to sea-level as adults (>16 years old). Exercise testing was conducted using a submaximal exercise protocol in normobaric hypoxia in Lima (BP=750 mmHg, Fio(2)=0.12), in order to measure Sao(2) (%), ventilation (VE L/min) and oxygen consumption (Vo(2), L/min). Repeated-measures ANOVA, controlling for VE/VO(2) (L/min) and sex during the submaximal protocol showed that BHA maintained higher Sao(2) (%) compared to BSL at all workloads before (p=0.005) and after training (p=0.017). As expected, both groups showed a decrease in Sao(2) (%) (p<0.001), as workload increased. Resting Sao(2) levels were not found to be different between groups. The results suggest that developmental exposure to altitude contributes to the maintenance of higher Sao(2) levels during submaximal exercise at hypoxia.
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Mal de Altura/metabolismo , Altitud , Indígenas Sudamericanos , Consumo de Oxígeno/fisiología , Intercambio Gaseoso Pulmonar/fisiología , Aclimatación/fisiología , Adolescente , Adulto , Prueba de Esfuerzo , Femenino , Humanos , Masculino , Perú/etnología , Adulto JovenRESUMEN
Intermittent hypobaric hypoxia (IH) is linked with oxidative stress, impairing cardiac function. However, early IH also activate cardio-protective mechanisms. Omega 3 fatty acids (Ω3) induce cardioprotection by reducing infarct size and reinforcing antioxidant defenses. The aim of this work was to determine the combined effects of IH and Ω3 on cardiac function; oxidative balance and inflammatory state. Twenty-eight rats were randomly divided into four groups: normobaric normoxia (N); N + Ω3 (0.3 g·kg-1·day-1); IH; and IH + Ω3. IH was induced by 4 intercalate periods of hypoxia (4 days)-normoxia (4 days) in a hypobaric chamber during 32 days. At the end of the exposure, hearts were mounted in a Langendorff system and subjected to 30 min of ischemia followed by 120 min of reperfusion. In addition, we determined HIF-1α and ATP levels, as well as oxidative stress by malondialdehyde and nitrotyrosine quantification. Further, the expression of the antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase was determined. NF-kappaB and myeloperoxidase levels were assessed in the hearts. Relative to N hearts, IH improved left ventricular function (Left ventricular developed pressure: N; 21.8 ± 3.4 vs. IH; 42.8 ± 7.1 mmHg; p < 0.05); reduced oxidative stress (Malondialdehyde: N; 14.4 ± 1.8 vs. IH; 7.3 ± 2.1 µmol/mg prot.; p < 0.05); and increased antioxidant enzymes expression. Supplementation with Ω3 induces similar responses as IH group. Our findings suggest that both, IH and Ω3 in an independent manner, induce functional improvement by antioxidant and anti-inflammatory mechanisms, establishing cardio-protection.
Asunto(s)
Mal de Altura/tratamiento farmacológico , Antioxidantes/farmacología , Cardiotónicos/farmacología , Ácidos Grasos Omega-3/uso terapéutico , Hipoxia/tratamiento farmacológico , Adenosina Trifosfato/metabolismo , Mal de Altura/metabolismo , Animales , Suplementos Dietéticos , Metabolismo Energético/efectos de los fármacos , Corazón/efectos de los fármacos , Hipoxia/complicaciones , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Técnicas In Vitro , Inflamación/metabolismo , Inflamación/prevención & control , Masculino , Miocardio/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
Chronic mountain sickness (CMS) or lack of adaptation to live in high altitudes is related to environmental hypoxia and excessive erythrocytosis (EE) (hemoglobin >21 and >19 g/dL for men and women, respectively). Diagnosis of CMS ("Qinghai CMS Score") is based on seven signs/symptoms (breathlessness and/or palpitations, sleep disturbance, cyanosis, dilatation of veins, paresthesia, headache, tinnitus) and the score for EE. The present study was designed to determine the association between hemoglobin, Qinghai CMS score, CMS clinical score (7 signs/symptoms) and Health Status using a health survey composed of 20 items. The rate of CMS (32.6%) was higher than the rate of EE (9.7%; P<0.002). A significant inverse relationship was observed between CMS clinical score and health status score (r=-0.56 for men, and r=-0.55 for women, P<0.01). However, CMS clinical score was not different in groups with different Hb levels. Health status score was significantly higher in subjects without CMS. In conclusion, elevated hemoglobin levels were not associated with elevated CMS clinical score.
Asunto(s)
Adaptación Fisiológica/fisiología , Mal de Altura/complicaciones , Mal de Altura/metabolismo , Altitud , Estado de Salud , Hemoglobinas/metabolismo , Índice de Severidad de la Enfermedad , Adulto , Anciano , Análisis de Varianza , Presión Sanguínea , Enfermedad Crónica , Estudios Transversales , Femenino , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Consumo de Oxígeno , Encuestas y CuestionariosRESUMEN
BACKGROUND: Acute exposure to high altitude stimulates free radical formation in lowlanders, yet whether this persists during chronic exposure in healthy, well-adapted and maladapted highlanders suffering from chronic mountain sickness (CMS) remains to be established. METHODS: Oxidative-nitrosative stress (as determined by the presence of the biomarkers ascorbate radical [A â¢- ], via electron paramagnetic resonance spectroscopy, and nitrite [NO 2 2 ], via ozone-based chemiluminescence) was assessed in venous blood of 25 male highlanders in Bolivia living at 3,600 m with CMS (n 5 13, CMS 1 ) and without CMS (n 5 12, CMS 2 ). Twelve age- and activity-matched, healthy, male lowlanders were examined at sea level and during acute hypoxia. We also measured fl ow-mediated dilatation (FMD), arterial stiffness defined by augmentation index normalized for a heart rate of 75 beats/min (AIx-75), and carotid intima-media thickness (IMT). RESULTS: Compared with normoxic lowlanders, oxidative-nitrosative stress was moderately increased in the CMS 2 group ( P , .05), as indicated by elevated A â¢- (3,191 457 arbitrary units [AU] vs 2,640 445 AU) and lower NO 2 2 (206 55 nM vs 420 128 nM), whereas vascular function remained preserved. This was comparable to that observed during acute hypoxia in lowlanders in whom vascular dysfunction is typically observed. In contrast, this response was markedly exaggerated in CMS 1 group (A â¢- , 3,765 429 AU; NO 2 2 , 148 50 nM) compared with both the CMS 2 group and lowlanders ( P , .05). This was associated with systemic vascular dysfunction as indicated by lower ( P , .05 vs CMS 2 ) FMD (4.2% 0.7% vs 7.6% 1.7%) and increased AIx-75 (23% 8% vs 12% 7%) and carotid IMT (714 127 m M vs 588 94 m M). CONCLUSIONS: Healthy highlanders display a moderate, sustained elevation in oxidative-nitrosative stress that, unlike the equivalent increase evoked by acute hypoxia in healthy lowlanders, failed to affect vascular function. Its more marked elevation in patients with CMS may contribute to systemic vascular dysfunction.
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Mal de Altura/fisiopatología , Altitud , Sistema Cardiovascular/fisiopatología , Hipoxia/fisiopatología , Nitrosación/fisiología , Estrés Oxidativo/fisiología , Adaptación Fisiológica/fisiología , Mal de Altura/metabolismo , Antioxidantes/metabolismo , Bolivia , Grosor Intima-Media Carotídeo , Estudios de Casos y Controles , Radicales Libres/metabolismo , Frecuencia Cardíaca/fisiología , Humanos , Hipoxia/metabolismo , Masculino , Persona de Mediana Edad , Óxido Nítrico/metabolismoRESUMEN
Lung carbon monoxide (CO) transfer and pulmonary capillary blood volume (Vc) at high altitudes have been reported as being higher in native highlanders compared to acclimatised lowlanders but large discrepancies appears between the studies. This finding raises the question of whether hypoxia induces pulmonary angiogenesis. Eighteen highlanders living in Bolivia and 16 European lowlander volunteers were studied. The latter were studied both at sea level and after acclimatisation to high altitude. Membrane conductance (Dm(CO)) and Vc, corrected for the haemoglobin concentration (Vc(cor)), were calculated using the NO/CO transfer technique. Pulmonary arterial pressure and left atrial pressures were estimated using echocardiography. Highlanders exhibited significantly higher NO and CO transfer than acclimatised lowlanders, with Vc(cor)/VA and Dm(CO)/VA being 49 and 17% greater (VA: alveolar volume) in highlanders, respectively. In acclimatised lowlanders, Dm(CO) and Dm(CO)/VA values were lower at high altitudes than at sea level. Echocardiographic estimates of cardiac output and pulmonary arterial pressure were significantly elevated at high altitudes as compared to sea level. The decrease in Dm(CO) in lowlanders might be due to altered gas transport in the airways due to the low density of air at high altitudes. The disproportionate increase in Vc in Andeans compared to the change in Dm(CO) suggests that the recruitment of capillaries is associated with a thickening of the blood capillary sheet. Since there was no correlation between the increase in Vc and the slight alterations in haemodynamics, this data suggests that chronic hypoxia might stimulate pulmonary angiogenesis in Andeans who live at high altitudes.
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Altitud , Volumen Sanguíneo , Capilares/fisiopatología , Hipertensión Pulmonar/fisiopatología , Pulmón/fisiopatología , Adulto , Mal de Altura/metabolismo , Mal de Altura/fisiopatología , Bolivia , Membrana Celular/metabolismo , Estudios Transversales , Femenino , Humanos , Hipertensión Pulmonar/complicaciones , Hipertensión Pulmonar/diagnóstico , Pulmón/irrigación sanguínea , Masculino , Capacidad de Difusión Pulmonar , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Hypobaric hypoxia (HH), an environmental condition of high altitude encountered by mountaineers, miners, and observatory, rural health, border patrol, and rural education workers, jeopardizes normal physiologic functions in humans. The present study was conducted to evaluate the effects of intermittent HH (IHH; equivalent to 4600 m above mean sea level) on oxidative stress and the protective role of dietary ascorbic acid on rat testis and epididymis. Ten-week-old male Wistar rats were assigned to 1 of 6 groups: 1) normobaric (Nx), 2) Nx + physiologic solution (Nx + PS), 3) Nx + ascorbic acid (Nx + AA), 4) IHH, 5) IHH + PS, or 6) IHH + AA. Animals subjected to IHH were exposed for 96 hours followed by normobaric conditions for 96 hours for a total of 32 days. The control groups (2 and 5) were injected with doses of PS, and the treated groups (3 and 6) were injected with doses of AA (10 mg x kg(-1) body weight) at an interval of 96 hours. Rats were sacrificed on day 32 after initiation of the protocol. The testis and epididymis were collected to determine the activity and expression of glutathione reductase and the levels of lipid peroxide formation. An epididymal sperm count was also performed in each animal. The results of this study revealed that IHH induced lipid peroxidation, a reduction in glutathione reductase activity in testis and epididymis, and a significant decrease in epididymal sperm count. Treatment with AA prevented these changes. In conclusion, AA was capable of decreasing oxidative stress in testis and epididymis under IHH. This protection by AA of the IHH-induced lipid peroxidation can be explained in part by the preservation of glutathione reductase activity in these organs.
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Mal de Altura/metabolismo , Ácido Ascórbico/farmacología , Epidídimo/metabolismo , Estrés Oxidativo/efectos de los fármacos , Testículo/metabolismo , Mal de Altura/prevención & control , Animales , Dieta , Glutatión Reductasa/metabolismo , Hipoxia/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ratas , Ratas Wistar , Recuento de EspermatozoidesRESUMEN
Chronic mountain sickness (CMS) is characterized by excessive erythrocytosis (EE) secondary to hypoventilation. Erythropoietin (Epo) and testosterone regulate erythrocyte production. Low thyroid hormone levels are also associated to hypoventilation. Hence, these hormones can play a role in etiopathogeny of EE. The purpose of this study was to elucidate the effect of sexual and thyroid hormones and Epo in residents from Lima (150 m) and Cerro de Pasco (4,340 m), Peru, and the response to human chorionic gonadotrophin stimulation (hCG). Three groups, one at low altitude and two at high altitude [1 with hemoglobin values >16-21 g/dl and the second with Hb >or=21 g/dl (EE)], were studied. hCG was administered intramuscularly in a single dose (1,000 IU), and blood samples were obtained at 0, 6, 12, 24, 48, and 72 h after injection. High-altitude natives present similar levels of gonadotropins and thyroid hormones but lower dehydroepiandrosterone sulphate (DHEAS) levels (P < 0.01) and greater Epo (P < 0.01), 17alpha-hydroxyprogesterone (P < 0.01), and testosterone levels (P < 0.01) than those at 150 m. Serum testosterone levels (524.13 +/- 55.91 microg/dl vs. 328.14 +/- 53.23 ng/dl, means +/- SE; P < 0.05) and testosterone/DHEAS ratios are higher (7.98 +/- 1.1 vs. 3.65 +/- 1.1; P < 0.01) and DHEAS levels lower in the EE group (83.85 +/- 14.60 microg/dl vs. 148.95 +/- 19.11 ug/dl; P < 0.05), whereas Epo was not further affected. Testosterone levels were highest and DHEAS levels lowest in the EE group at all times after hCG stimulation. In conclusion, high androgen activity could be involved in the etiopathogeny of CMS. This evidence provides an opportunity to develop new therapeutic strategies.
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Mal de Altura/etiología , Mal de Altura/metabolismo , Eritrocitos/metabolismo , Policitemia/etiología , Policitemia/metabolismo , Testosterona/sangre , 17-alfa-Hidroxiprogesterona/sangre , Adulto , Anciano , Altitud , Enfermedad Crónica , Sulfato de Deshidroepiandrosterona/sangre , Eritrocitos/citología , Eritropoyetina/sangre , Estradiol/sangre , Hematócrito , Hemoglobinas/metabolismo , Humanos , Masculino , Persona de Mediana Edad , PerúRESUMEN
BACKGROUND: Life at altitude depends on adaptation to ambient hypoxia. In the Andes, susceptibility to chronic mountain sickness (CMS), a clinical condition that occurs to native highlanders or to sea level natives with prolonged residence at high altitude, remains poorly understood. We hypothesized that hypoxia-associated gene expression in children of men with CMS might identify markers that predict the development of CMS in adults. We assessed distinct patterns of gene expression of hypoxia-responsive genes in children of highland Andean men, with and without CMS. METHODS: We compared molecular signatures in children of highland (HA) men with CMS (n = 10), without CMS (n = 10) and in sea level (SL) children (n = 20). Haemoglobin, haematocrit, and oxygen saturation were measured. Gene expression in white cells was assessed at HA and then, in the same subjects, within one hour of arrival at sea level. RESULTS: HA children showed higher expression levels of genes regulated by HIF (hypoxia inducible factor) and lower levels of those involved in glycolysis and in the tricarboxylic acid (TCA) cycle. Pyruvate dehydrogenase kinase 1(PDK1) and HIF prolyl hydroxylase 3 (HPH3) mRNA expressions were lowest in children of CMS fathers at altitude. At sea level the pattern of gene expression in the 3 children's groups was indistinguishable. CONCLUSION: The molecular signatures of children of CMS patients show impaired adaptation to hypoxia. At altitude children of CMS fathers had defective coupling between glycolysis and mitochondria TCA cycle, which may be a key mechanism/biomarker for adult CMS. Early biologic markers of disease susceptibility in Andeans might impact health services and social planning.
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Mal de Altura/fisiopatología , Altitud , Metabolismo Energético/fisiología , Hipoxia/fisiopatología , Adaptación Fisiológica/genética , Adaptación Fisiológica/fisiología , Adolescente , Adulto , Mal de Altura/genética , Mal de Altura/metabolismo , Niño , Preescolar , Enfermedad Crónica , Ciclo del Ácido Cítrico/fisiología , Estudios Transversales , Dioxigenasas/genética , Metabolismo Energético/genética , Expresión Génica , Glucólisis/fisiología , Hematócrito , Hemoglobina A/análisis , Humanos , Prolina Dioxigenasas del Factor Inducible por Hipoxia , Masculino , Valor Predictivo de las Pruebas , Proteínas Serina-Treonina Quinasas/genética , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Hypoxia is implicated in aging and neurodegenerative diseases. We posited that changes in gene expression induced by ambient hypoxia at altitude may be neuroprotective to natives of these regions. We studied 30 men. Twenty natives of Cerro de Pasco (CP), altitude 4,338 m were examined in CP; then transported within 6 h to Lima (150 m-sea level) and examined 1 h after arrival. They were assessed by a Chronic Mountain Sickness-score (CMS-sc) in CP, 10 were normal Andeans and 10 had chronic mountain sickness (CMS), a sudden inexplicable loss of adaptation to their native environment. RNA was extracted from venous blood white cells. The Andeans were compared to 10 normal US men living at 1500 m using RT-PCR. We focused on the cyto-neuro-protective genes, Ataxia telangiectasia mutated (ATM), heme-oxygenase-1 (HMOX 1), heat shock protein-70 (HSP-70), heat shock protein-90 (HSP-90), and the neuroprotective enzyme, nicotinamide mononucleotide adenylyl transferase 1 (Nnmat 1). CMS patients had significantly higher levels of gene expression (HMOX-1, HSP-70, ATM) than Andean controls in CP. HSP-90 and Nmnat 1, however, were higher in Andean controls in all locations. Significant reductions of all gene products, within an hour of arriving in normoxia in Lima, were found. In Andean controls, the gene products in Lima fell to levels approaching US controls. Correlation and regression methods showed men with high expression of all gene products had an average CMS-sc=19.8; those with low expression a normal score (9.4, P=0.02). ATM expression was related to age (P<0.001). The natural experiment that unfolds in the mountainous regions of the world provides opportunities to study neuroprotection in intact humans.
Asunto(s)
Altitud , Perfilación de la Expresión Génica , Hipoxia/fisiopatología , Adaptación Fisiológica , Envejecimiento/metabolismo , Mal de Altura/metabolismo , Mal de Altura/fisiopatología , Mal de Altura/prevención & control , Enfermedad Crónica , Humanos , Hipoxia/metabolismo , Hipoxia/prevención & control , Masculino , Perú , Valores de Referencia , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Autonomic function is altered by altitude in sojourners and natives. We hypothesized that these physiologic responses are modulated by changes in gene expression. We compared gene product levels in 20 natives of Cerro de Pasco (CP), (4338 m), 10 of which had chronic mountain sickness (CMS) established by a CMS-scoring system, with gene products in the same men after 1 h at sea level. We further compared the results with those obtained from 10 US men residing at 1500 m. We measured gene products in white cells by reverse transcription polymerase chain reaction (RT-PCR). We focused on genes important in vascular autonomic physiology, and/or activated by hypoxia; hypoxia inducible factor 1-alpha (HIF 1-alpha), 2 splicing variants of vascular endothelial growth factor (VEGF); VEGF-121, VEGF-165, and phosphoglycerate kinase 1 (PGK 1). Normal CP natives showed high expression of all genes in CP, compared to US controls. Within 1 h of arrival at sea level, they had comparable levels to US residents. In CMS, the gene products were higher in CP. Although gene products decreased in Lima in this group, they never reached US values. VEGF 121 and 165 were correlated (P<0.001). VEGF 165 was higher in CMS in CP (P=0.006), and was positively correlated with CMS-score (R=0.86, P<0.001), and negatively correlated with arterial saturation (R=-0.79, P<0.001). Our findings underscore the changes in gene expression levels in intact humans in response to environmental stress. These changes may support the physiologic alterations induced by the ambient hypoxia at altitude and impact organism survival. They also suggest therapeutic strategies for autonomic and neurodegenerative diseases at sea level.
Asunto(s)
Mal de Altura/fisiopatología , Sistema Nervioso Autónomo/fisiopatología , Regulación de la Expresión Génica , Hipoxia/fisiopatología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Adaptación Fisiológica , Adulto , Altitud , Mal de Altura/genética , Mal de Altura/metabolismo , Enfermedad Crónica , Humanos , Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Leucocitos/metabolismo , Masculino , Persona de Mediana Edad , Perú , Fosfoglicerato Quinasa/clasificación , Fosfoglicerato Quinasa/genética , Fosfoglicerato Quinasa/metabolismo , Estados Unidos , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
Lung oxidative stress (OS) was explored in resting and in exercising subjects exposed to moderate and high altitude. Exhaled breath condensate (EBC) was collected under field conditions in male high-competition mountain bikers performing a maximal cycloergometric exercise at 670 m and at 2,160 m, as well as, in male soldiers climbing up to 6,125 m in Northern Chile. Malondialdehyde concentration [MDA] was measured by high-performance liquid chromatography in EBC and in serum samples. Hydrogen peroxide concentration [H(2)O(2)] was analysed in EBC according to the spectrophotometric FOX(2) assay. [MDA] in EBC of bikers did not change while exercising at 670 m, but increased from 30.0+/-8.0 to 50.0+/-11.0 nmol l(-1) (P<0.05) at 2,160 m. Concomitantly, [MDA] in serum and [H(2)O(2)] in EBC remained constant. On the other hand, in mountaineering soldiers, [H(2)O(2)] in EBC under resting conditions increased from 0.30+/-0.12 mumol l(-1) at 670 m to 1.14+/-0.29 mumol l(-1) immediately on return from the mountain. Three days later, [H(2)O(2)] in EBC (0.93 +/-0.23 mumol l(-1)) continued to be elevated (P<0.05). [MDA] in EBC increased from 71+/-16 nmol l(-1) at 670 m to 128+/-26 nmol l(-1) at 3,000 m (P<0.05). Changes of [H(2)O(2)] in EBC while ascending from 670 m up to 3,000 m inversely correlated with concomitant variations in HbO2 saturation (r=-0.48, P<0.05). AMS score evaluated at 5,000 m directly correlated with changes of [MDA] in EBC occurring while the subjects moved from 670 to 3,000 m (r=0.51, P<0.05). Lung OS may constitute a pathogenic factor in AMS.
Asunto(s)
Mal de Altura/diagnóstico , Mal de Altura/metabolismo , Altitud , Pulmón/metabolismo , Estrés Oxidativo/fisiología , Adolescente , Adulto , Pruebas Respiratorias , Ejercicio Físico/fisiología , Prueba de Esfuerzo , Humanos , Peróxido de Hidrógeno/metabolismo , Peroxidación de Lípido , Masculino , Malondialdehído/metabolismo , Montañismo/fisiologíaRESUMEN
The generation of reactive oxygen species is typically associated with hyperoxia and ischemia reperfusion. Recent evidence has suggested that increased oxidative stress may occur with hypoxia. We hypothesized that oxidative stress would be increased in subjects exposed to high altitude hypoxia. We studied 28 control subjects living in Lima, Peru (sea level), at baseline and following 48 h exposure to high altitude (4300 m). To assess the effects of chronic altitude exposure, we studied 25 adult males resident in Cerro de Pasco, Peru (altitude 4300 m). We also studied 27 subjects living in Cerro de Pasco who develop excessive erythrocytosis (hematocrit > 65%) and chronic mountain sickness. Acute high altitude exposure led to increased urinary F(2)-isoprostane, 8-iso PGF(2 alpha) (1.31 +/- 0.8 microg/g creatinine versus 2.15 +/- 1.1, p = 0.001) and plasma total glutathione (1.29 +/- 0.10 micromol versus 1.37 +/- 0.09, p = 0.002), with a trend to increased plasma thiobarbituric acid reactive substance (TBARS) (59.7 +/- 36 pmol/mg protein versus 63.8 +/- 27, p = NS). High altitude residents had significantly elevated levels of urinary 8-iso PGF(2 alpha) (1.3 +/- 0.8 microg/g creatinine versus 4.1 +/- 3.4, p = 0.007), plasma TBARS (59.7 +/- 36 pmol/mg protein versus 85 +/- 28, p = 0.008), and plasma total glutathione (1.29 +/- 0.10 micromol versus 1.55 +/- 0.19, p < 0.0001) compared to sea level. High altitude residents with excessive erythrocytosis had higher levels of oxidative stress compared to high altitude residents with normal hematological adaptation. In conclusion, oxidative stress is increased following both acute exposure to high altitude without exercise and with chronic residence at high altitude.
Asunto(s)
Aclimatación , Mal de Altura/complicaciones , Mal de Altura/metabolismo , Altitud , Dinoprostona/análogos & derivados , Peroxidación de Lípido , Estrés Oxidativo , Enfermedad Aguda , Adulto , Mal de Altura/fisiopatología , Enfermedad Crónica , Dinoprostona/orina , F2-Isoprostanos/orina , Glutatión/sangre , Hemodinámica , Humanos , Hipertensión Pulmonar/etiología , Isoprostanos/orina , Masculino , Persona de Mediana Edad , Perú , Policitemia/etiología , Factores de Riesgo , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo , Disfunción Ventricular Derecha/etiologíaRESUMEN
Headache is common in Cerro de Pasco (CP), Peru (altitude 4338 m) and was present in all patients with chronic mountain sickness (CMS) in CP reported here. Forty-seven percent of inhabitants report headache. Twenty-four percent of men have migraine with aura, with an average of 65 attacks a year. We assessed vasoreactivity of the cerebral vessels to CO2 by rebreathing and to NO by the administration of isosorbite dinitrate (IDN), a nitric oxide (NO) donor, using transcranial Doppler ultrasound in the middle cerebral artery (MCA) in natives of CP, some of whom suffered from CMS. We repeated the measurements in Lima (altitude 150 m) in the same subjects within 24 h of arrival. Vasodilatation in the middle cerebral artery supply territory in response to CO2 and NO, both physiologic vasodilators, is defective in Andean natives at altitude and in the same subjects at sea level. Incapacitating migraine can occur with impaired cerebral vasoreactivity to physiologic vasodilators. We propose that susceptibility to migraine might depend in part on gene expression with consequent alterations of endothelial function.
Asunto(s)
Mal de Altura/fisiopatología , Altitud , Circulación Cerebrovascular/fisiología , Migraña con Aura/fisiopatología , Mal de Altura/diagnóstico por imagen , Mal de Altura/metabolismo , Dióxido de Carbono/metabolismo , Enfermedad Crónica , Humanos , Masculino , Arteria Cerebral Media/diagnóstico por imagen , Arteria Cerebral Media/fisiología , Migraña con Aura/diagnóstico por imagen , Migraña con Aura/metabolismo , Óxido Nítrico/metabolismo , Perú , Ultrasonografía Doppler TranscranealRESUMEN
Chronic mountain sickness (CMS), a maladaptation syndrome to chronic hypoxia, occurs in the Andes. Gene expression differences in Andeans could explain adaptation and maladaptation to hypoxia, both of which are relevant to neurology at sea level. Expression of genes responsive to cellular oxygen concentration, hypoxia-inducible factor-1alpha (HIF-1alpha), three splicing variants of vascular endothelial growth factor (VEGF) and von Hippel-Lindau protein (pVHL) was measured by reverse transcription polymerase chain reaction (RT-PCR) in 12 Cerro de Pasco (CP) (altitude 4338 m) natives and 15 CMS patients in CP. Thirteen high altitude natives living in Lima and five Lima natives were sea level controls. A CMS score (CMS-sc) was assigned clinically. Expression was related to the clinical assessment. High expression of HIF-1alpha and VEGF-121 was found in CMS (P<0.001). Samples from CP had higher expression than those from Lima (P<0.001). Expression of HIF-1alpha and VEGF-121 was related to age (P<0.001); adjusting for age did not abolish the group effect. Higher CMS-sc was related to expression independent of age (P<0.001). VEGF-165 and -189 were expressed only in CMS. Birth altitude had no effect on gene expression. pVHL was not quantifiable.HIF-1alpha and VEGF-121 participate in adaptation to hypoxia. The high levels may explain blood vessel proliferation in Andeans and hold lessons for patients at sea level. VEGF-165 expression suggests that it contributes to preservation of neuronal function in human chronic hypoxia. VHL mutations may mark those destined to develop neural crest tumors which are common in the Andes.
Asunto(s)
Mal de Altura/metabolismo , Altitud , Regulación de la Expresión Génica/fisiología , Factores de Transcripción , Adulto , Mal de Altura/genética , Mal de Altura/fisiopatología , Análisis de Varianza , Proteínas de Unión al ADN/biosíntesis , Factores de Crecimiento Endotelial/biosíntesis , Humanos , Factor 1 Inducible por Hipoxia , Subunidad alfa del Factor 1 Inducible por Hipoxia , Péptidos y Proteínas de Señalización Intercelular/biosíntesis , Linfocinas/biosíntesis , Masculino , Persona de Mediana Edad , Proteínas Nucleares/biosíntesis , Perú/epidemiología , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial VascularRESUMEN
BACKGROUND: Thirty-nine percent of permanent altitude dwellers in the Andes experience acral paresthesias. METHODS: Clinical examinations, sural nerve biopsies, and electrodiagnostic studies on peripheral nerves were performed on 15 men. Ten Cerro de Pasco (CP) natives living at 4,338 meters were biopsied. Three of these subjects had no burning feet/burning hands (BF/BH); three had BF/BH; and four had chronic mountain sickness (CMS), a maladaptation syndrome resulting from living in the Andes, all with BF/BH. Three patients with CMS were biopsied in Lima within hours after leaving CP. Two normal Lima natives were biopsied in Lima. Symptom scores for BF/BH and CMS score ratings were used. The nerves were assayed for Na+, K+ adenosine triphosphatase (ATPase), cytochrome oxidase (CO), substance P (SP), and endothelin (ET). RESULTS: Low ATPase was inversely related to symptom scores and CMS scores (p < 0.001). Patients with CMS biopsied in normoxia (Lima) had ATPase levels similar to those of controls. Nerve motor conduction velocities and sensory action potentials were normal. CO was inversely related to age (p < 0.03) and no relation of SP to any variable was found. ET levels were lower in sea level natives (p = 0.04). CONCLUSIONS: Acral paresthesias are associated with low ATPase in peripheral nerves. Lower ET levels of sea level natives likely reflect lowered release from vasa nervorum.