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

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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.