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Neocytolysis: Quantification, characterization, and mechanisms of the destruction of newly formed erythrocytes upon return from high altitude

新细胞溶解：从高海拔返回后新形成的红细胞破坏的定量、表征和机制

基本信息

批准号：
402842496
负责人：
Professor Dr. Lars Kaestner
金额：
--
依托单位：
Abteilung Innere Medizin VII: Sportmedizin
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2018
资助国家：
德国
起止时间：
2017-12-31 至 2020-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/402842496?language=en
关键词：
Neocytolysis Quantification characterization mechanisms destruction

项目摘要

Erythrocytes formed during exposure to hypoxia at high altitude seem to be destroyed preferentially within a few days upon return to normoxia in order to reduce the number of circulating erythrocytes. This process has been termed “neocytolysis”. Experimental evidence from studies on human mountaineers is weak, but there is recent evidence for neocytolysis on mice. Neocytolysis seems to occur upon withdrawal of erythropoietin. However, direct experimental proof in humans is lacking. Neocytolysis is of significant clinical interest because it might adversely affect the outcome of patients receiving erythropoietin to treat renal anemia. Neocytolysis might also explain the variable results on improved performance of athletes after training in hypoxic environments, which athletes choose to increase oxygen transport capacity.It is the primary goal of this study to prove that neocytolysis actually occurs in humans. Therefore, subjects will be exposed to hypoxia at high altitude (3450m) for 3 weeks to induce production of sufficient amounts of new erythrocytes allowing their detection, but also their rate of destruction after entering circulation and their overall life-span. The amount of newly formed erythrocytes will be measured by indicator dilution using a carbon-monoxide rebreathing technique. Age-cohort labeling of newly formed erythrocytes will be performed by intake of 15N-glycine (pre-altitude) and 13C-2-glycine (post altitude), respectively, where the amount of newly formed cells in circulation will be detected from the ratio of 15N/14N and 13C/12C, measured by mass spectroscopy in heme isolated from whole blood. Furthermore, markers of hemolysis will be determined. Additional goals of this project are: clarifying differences in function of erythrocytes that had been formed in hypoxia relative to those formed in a normoxic environment, and, based on this, to define mechanisms that might explain their susceptibility for premature destruction. Those experiments will include measurements of parameters indicating oxidative stress, erythrocyte Ca2+-homeostasis that might be involved in cell lysis. Such measurements will be performed on freshly isolated reticulocytes and erythrocytes, as well as on erythroid stem cells cultured and studied in vitro.

在高海拔暴露于缺氧期间形成的红细胞似乎在恢复常氧后的几天内优先被破坏，以减少循环红细胞的数量。该过程被称为“新细胞溶解”。对人类登山运动员的研究的实验证据很弱，但最近有证据表明小鼠的新细胞溶解。停用促红细胞生成素后似乎发生新细胞溶解。然而，在人类中缺乏直接的实验证据。新细胞溶解具有重要的临床意义，因为它可能对接受促红细胞生成素治疗肾性贫血的患者的结果产生不利影响。新细胞溶解也可以解释运动员在低氧环境中训练后表现改善的可变结果，运动员选择增加氧运输能力。因此，受试者将在高海拔（3450 m）暴露于缺氧3周，以诱导产生足量的新红细胞，从而允许检测它们，以及它们进入循环后的破坏率和它们的总体寿命。使用一氧化碳再呼吸技术通过指示剂稀释测量新形成红细胞的量。分别通过摄入15 N-甘氨酸（海拔前）和13 C-2-甘氨酸（海拔后）对新形成的红细胞进行双队列标记，其中将根据15 N/14 N和13 C/12 C的比率检测循环中新形成细胞的量，通过质谱法在从全血分离的血红素中测量。此外，还将测定溶血标志物。该项目的其他目标是：澄清在低氧环境中形成的红细胞相对于在常氧环境中形成的红细胞在功能上的差异，并在此基础上定义可能解释其过早破坏的易感性的机制。这些实验将包括指示氧化应激、红细胞Ca 2+稳态的参数的测量，这些参数可能参与细胞溶解。将对新鲜分离的网织红细胞和红细胞以及体外培养和研究的红系干细胞进行此类测量。