RESUMEN
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.
Asunto(s)
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
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.
Asunto(s)
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
We used transgenic mice constitutively over-expressing erythropoietin ("tg6" mice) and wild-type (wt) mice to investigate whether the high hematocrit (hct), consequence of Epo over-expression affected: (1) the normoxic ventilation (V (E)) and the acute hypoxic ventilatory response (HVR) and decline (HVD), (2) the increase in ventilation observed after chronic exposure to hypobaric hypoxia (430mmHg for 21 days), (3) the respiratory "blunting", and (4) the erythrocythemic response induced by chronic hypoxia exposure. V (E) was found to be similar in tg6 and wt mice in normoxia (FIO2=0.21). Post-acclimation V (E) was significantly elevated in every time point in wt mice at FIO2=0.10 when compared to pre-acclimation values. In contrast, tg6 mice exhibited a non-significant increase in V (E) throughout acute hypoxia exposure. Changes in V (E) are associated with adjustments in tidal volume (V(T)). HVR and HVD were independent of EE in tg6 and wt mice before chornic hypoxia exposure. HVR was significantly greater in wt than in tg6 mice after chronic hypoxia. After acclimation, HVD decreased in tg6 mice. Chronic hypoxia exposure caused hct to increase significantly in wt mice, while only a marginal increase occurred in the tg6 group. Although pre-existent EE does not appear to have an effect on HVR, the observation of alterations on V(T) suggests that it may contribute to time-dependent changes in ventilation and in the acute HVR during exposure to chronic hypoxia. In addition, our results suggest that EE may lead to an early "blunting" of the ventilatory response.
Asunto(s)
Aclimatación/fisiología , Eritropoyetina/metabolismo , Hipoxia/metabolismo , Policitemia/metabolismo , Ventilación Pulmonar/fisiología , Aclimatación/genética , Animales , Eritropoyetina/genética , Femenino , Hematócrito , Hemoglobinas/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Consumo de Oxígeno/fisiología , Policitemia/genética , Volumen de Ventilación Pulmonar/fisiologíaRESUMEN
Stress erythropoiesis is usually considered as a compensatory effort to counteract tissue hypoxia. Its homeostatic importance in anemic hypoxia has not been questioned, but researchers, clinicians, and mountain climbers have had second thoughts on polycythemia as to its appropriateness for hypoxic or altitude hypoxia (HA). Therefore, polycythemia, one of the responses to HA seen in nongenetically adapted mammals, could or could not be considered beneficial. The present study was thus performed to obtain further information on the importance of HA polycythemia on acclimation of mice to HA. To this end, the development of polycythemia was prevented by experimental manipulations (administration of 20 mg/kg/d of the hemolytic drug phenylhydrazine or removal of 0.225 mL/d of blood), and the degree of tissue hypoxia was evaluated from plasma erythropoietin (pEPO) concentration, as determined by immunoassay, in adult female mice exposed to air maintained at 506 mbar (380 mmHg) in a simulated HA (SHA) chamber during at least 23.5 h/d for 9 d. Plasma EPO concentration in those treated hypoxic mice whose hematocrit values remained almost unchanged was between 5.55 and 7.89 times higher (depending on the experimental designs) than in control hypoxic mice allowed to develop HA polycythemia. These results, plus the finding of an inverse relationship between the hematocrit value and pEPO concentration in both the polycythemic and normocythemic SHA-exposed mice indicate that HA polycythemia is highly effective in ameliorating tissue hypoxia under SHA conditions, thus giving support to the concept of the important role of the increased hemoglobin mass in nongenetically adapted animals, whereas a left-shifted oxyhemoglobin dissociation curve confers a good degree of adaptation to HA in genetically adapted animals.
Asunto(s)
Mal de Altura/sangre , Eritropoyesis/efectos de los fármacos , Eritropoyetina/biosíntesis , Fenilhidrazinas/farmacología , Policitemia/metabolismo , Análisis de Varianza , Animales , Cámaras de Exposición Atmosférica , Presión Atmosférica , Hipoxia de la Célula/efectos de los fármacos , Hipoxia de la Célula/fisiología , Eritropoyetina/sangre , Eritropoyetina/metabolismo , Femenino , Hematócrito , Inmunoensayo , Ratones , Tasa de Secreción/efectos de los fármacosRESUMEN
Hb Johnstown [beta109(G11)Val-->Leu], a high oxygen affinity hemoglobin (Hb) variant associated with beta0-thalassemia (thal) [IVS-I-1 (G-->A)], was identified in an 8-year-old girl referred to our laboratory because of erythrocytosis and a left-shifted oxygen dissociation curve (ODC). The phylogenetic tree showed that the mother was heterozygous for the Hb variant and the father was a beta0-thal carrier. This Hb variant, with normal electrophoresis, was characterized at the DNA level by beta gene sequencing. The amino acid substitution potentially disrupts alpha1beta1 contacts i n the deoxyHb conformation, thus shifting the equilibrium towards the high affinity oxyHb conformation. The erythrocytosis and low values for actual P50 due to Hb Johnstown were more marked due to the co-inheritance of the beta0-thal.
Asunto(s)
Hemoglobinas Anormales/genética , Oxígeno/metabolismo , Talasemia beta/genética , Niño , Femenino , Hemoglobinas Anormales/metabolismo , Humanos , Padres , Policitemia/complicaciones , Policitemia/metabolismo , Talasemia beta/complicaciones , Talasemia beta/metabolismoRESUMEN
A simple in vivo bioassay suitable for routine testing of quality control of recombinant human erythropoietin (rHu-EPO) analogues was developed. Mice made polycythemic by intraperitoneal injection of 1.2 ml of a 80% suspension of heterologous (rat) red cells were used as assay animals and splenic 59Fe uptake as expression of the response to rHu-EPO. The assay took three days and the following schedule is proposed: 1) intraperitoneal injection of 1.2 ml of washed packed red cells obtained from donor rats, 2) subcutaneous injection of test material 4-5 h after transfusion, 3) intravenous administration of 59Fe tracer 48 h later, and 4) determination of splenic isotope uptake 6 h after injection. This method for the in vivo bioassay of rHu-EPO analogues is an economical and reliable alternative to the existing bioassays of the hormone.
Asunto(s)
Transfusión de Eritrocitos , Eritropoyetina/análisis , Policitemia/metabolismo , Animales , Bioensayo , Eritropoyesis , Femenino , Radioisótopos de Hierro , Ratones , Policitemia/etiología , Ratas , Ratas Wistar , Proteínas RecombinantesRESUMEN
A simple in vivo bioassay suitable testing of quality control of recombinant human erythropoietin (rHu-EPO) analogues was developed. Mice made polycythemic by intraperitoneal injection of 1.2 ml of a 80 per cent suspension of heterologous (rat) red cells were used as assay animals and splenic 59 Fe uptke as expression of the response to rHu-EPO. The assay took three days and the following schedule is propose: 1)intraperitoneal injection of 1.2 ml of washed packed red cells obtained from donor rats, 2) subcutaneous injection of test material 4-5 h after transfusion, 3) intravenous administration of 59 Fe tracer 48 h later, and 4) determination of splenic isotope uptake 6 h after injection. This method for the in vivo biossay of rHu-EPO analogues is an economical and reliable alternative to the existing bioassays of the hormone
Asunto(s)
Animales , Ratones , Ratas , Femenino , Transfusión de Eritrocitos , Eritropoyetina/análisis , Policitemia/metabolismo , Bioensayo , Eritropoyesis , Radioisótopos de Hierro , Policitemia/etiología , Radiactividad , Ratas WistarRESUMEN
A simple in vivo bioassay suitable testing of quality control of recombinant human erythropoietin (rHu-EPO) analogues was developed. Mice made polycythemic by intraperitoneal injection of 1.2 ml of a 80 per cent suspension of heterologous (rat) red cells were used as assay animals and splenic 59 Fe uptke as expression of the response to rHu-EPO. The assay took three days and the following schedule is propose: 1)intraperitoneal injection of 1.2 ml of washed packed red cells obtained from donor rats, 2) subcutaneous injection of test material 4-5 h after transfusion, 3) intravenous administration of 59 Fe tracer 48 h later, and 4) determination of splenic isotope uptake 6 h after injection. This method for the in vivo biossay of rHu-EPO analogues is an economical and reliable alternative to the existing bioassays of the hormone(AU)
Asunto(s)
Animales , Ratones , Ratas , Femenino , RESEARCH SUPPORT, NON-U.S. GOVT , Eritropoyetina/análisis , Policitemia/metabolismo , Transfusión de Eritrocitos , Bioensayo , Eritropoyesis , Ratas Wistar , Policitemia/etiología , Radiactividad , Radioisótopos de HierroRESUMEN
A ferrokinetic study was performed in 79 patients, 25 with absolute polycythaemia, 19 with relative polycythaemia and 35 presenting anaemia of different aetiology. The incorporation of transferrin into the erythron (ITE) was estimated on each case. The mean ITE values found in absolute primary and secondary polycythaemia and in secondary polycythaemia were, respectively, 281 +/- 85, 181 +/- 99 and 74 +/- 19 mumol/L tb/d (i.e., micromoles per litre of total blood per day). The mean ITE in iron deficiency anaemia was 110 +/- 43 mumol/L tb/d, in haemolytic anaemia this was 274 +/- 151 mumol/L tb/d, and in patients with myelodysplastic syndromes such values was 116 +/- 49 mumol/L tb/d. Significant differences were found for each group of patients with respect to a normal control group. Such findings are in accordance with the pathophysiology of the different pathologies studied. The values found in haemolytic anaemia and myelodysplastic syndromes are similar to those reported by others. The results of this study stress the advantages of evaluating the erythropoietic activity of the bone marrow by means of the ITE.