Modulation of red cell mass by neocytolysis in space and on Earth

Rice, Lawrence; Alfrey, Clarence P.

doi:10.1007/s004240000333

Cited by 42 publications

(23 citation statements)

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“…Thus, when altitude natives, or even altitude sojourners, return to sea level, there is a suppression of erythropoietin (Faura et al, 1969;Jelkman, 1992;Richalet et al, 1993;Gunga et al, 1996;Levine and Stray-Gundersen, 1997;Chapman et al, 1998), a dramatic reduction in iron turnover and bone marrow production of erythroid cell lines (Huff et al, 1951;Reynafarje et al, 1959), and a marked decrease in red cell survival time (Reynafarje et al, 1959). This increase in red cell destruction with suppression of EPO levels has been termed neocytolysis and has been observed under other conditions of a relative increase in oxygen content (Alfrey et al, 1996a(Alfrey et al, , 1996b(Alfrey et al, , 1997Rice and Alfrey, 2000;Rice et al, 2001). Both the rapid ubiquitination and destruction of HIF-1a and neocytolysis (which may be its clinical manifestation) may compromise the ability of short-duration, intermittent hypoxic exposures to induce a sustained increase in the red cell mass.…”

Section: Erythropoietic Effect Of High Altitudementioning

confidence: 97%

Intermittent Hypoxic Training: Fact and Fancy

Levine

2002

High Altitude Medicine & Biology

163

142

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LTITUD E TRAINING has been used frequently by endurance athletes to enhance performance. However, not all athletes or teams have the resources to travel to high altitude environments on a regular basis. Moreover, issues such as availability of adequate training facilities have limited the use of mountain-based altitude training. In the last few years, there has been a remarkable increase in the number of techniques designed to "bring the mountain to the athlete." Nitrogen houses, hypoxia tents, and special breathing apparatuses to provide inspired hypoxia at rest and during exercise, all have been developed and promoted to simulate what are perceived as the critical elements of altitude training.Intermittent hypoxic training (IHT) refers to the discontinuous use of normobaric or hypobaric hypoxia, in an attempt to reproduce some of these key features of altitude acclimatization, with the ultimate goal to improve sea-level athletic performance. In general, IHT can be divided into two different strategies: (1) providing hypoxia at rest with High Alt Med Biol. 3:177-193, 2002.-Intermittent hypoxic training (IHT) refers to the discontinuous use of normobaric or hypobaric hypoxia, in an attempt to reproduce some of the key features of altitude acclimatization, with the ultimate goal to improve sea-level athletic performance. In general, IHT can be divided into two different strategies: (1) providing hypoxia at rest with the primary goal being to stimulate altitude acclimatization or (2) providing hypoxia during exercise, with the primary goal being to enhance the training stimulus. Each approach has many different possible application strategies, with the essential variable among them being the "dose" of hypoxia necessary to achieve the desired effect. One approach, called living high-training low, has been shown to improve sea-level endurance performance. This strategy combines altitude acclimatization (2500 m) with low altitude training to ensure high-quality training. The opposite strategy, living low-training high, has also been proposed by some investigators. The primacy of the altitude acclimatization effect in IHT is demonstrated by the following facts: (1) living high-training low clearly improves performance in athletes of all abilities, (2) the mechanism of this improvement is primarily an increase in erythropoietin, leading to increased red cell mass, V O 2max , and running performance, and (3) rather than intensifying the training stimulus, training at altitude or under hypoxia leads to the opposite effect-reduced speeds, reduced power output, reduced oxygen flux-and therefore is not likely to provide any advantage for a well-trained athlete.

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Section: Erythropoietic Effect Of High Altitudementioning

confidence: 97%

Intermittent Hypoxic Training: Fact and Fancy

Levine

2002

High Altitude Medicine & Biology

163

142

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“…Proposed model of neocytolysis. Endothelial cells respond to changes in circulating EPO by influencing the interaction of phagocytes with young red blood cells, the latter targeted by surface adhesion molecules [25].…”

Section: Applicability To Other Physiologic and Pathophysiologic Situmentioning

confidence: 99%

The Negative Regulation of Red Cell Mass by Neocytolysis: Physiologic and Pathophysiologic Manifestations

Rice

Alfrey

2005

Cell Physiol Biochem

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155

124

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We have uncovered a physiologic process which negatively regulates the red cell mass by selectively hemolyzing young circulating red blood cells. This allows fine control of the number of circulating red blood cells under steady-state conditions and relatively rapid adaptation to new environments. Neocytolysis is initiated by a fall in erythropoietin levels, so this hormone remains the major regulator of red cell mass both with anemia and with red cell excess. Physiologic situations in which there is increased neocytolysis include the emergence of newborns from the hypoxic uterine environment and the descent of polycythemic high-altitude dwellers to sea level. The process first became apparent while investigating the mechanism of the anemia that invariably occurs after spaceflight. Astronauts experience acute central plethora on entering microgravity resulting in erythropoietin suppression and neocytolysis, but the reduced blood volume and red cell mass become suddenly maladaptive on re-entry to earth’s gravity. The pathologic erythropoietin deficiency of renal disease precipitates neocytolysis, which explains the prolongation of red cell survival consistently resulting from erythropoietin therapy and points to optimally efficient erythropoietin dosing schedules. Implications should extend to a number of other physiologic and pathologic situations including polycythemias, hemolytic anemias, ‘blood-doping’ by elite athletes, and oxygen therapy. It is likely that erythropoietin influences endothelial cells which in turn signal reticuloendothelial phagocytes to destroy or permit the survival of young red cells marked by surface molecules. Ongoing studies to identify the molecular targets and cytokine intermediaries should facilitate detection, dissection and eventual therapeutic manipulation of the process.

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“…However, the clearance of red cells and in particular of neocytes generated in normogravity, which occurs during the first days of spaceflight [7,8,12], or after EPO doping [11], are less likely due to specific features of defective red cells. It is more likely that their removal from circulating blood is strictly linked to EPO decline.…”

Section: Discussionmentioning

confidence: 99%

“…In high altitude polycythemic dwellers returning to a normoxic environment, a fast decrease in RBC mass is obtained by a decrease in EPO synthesis and by destruction of red cells [5,6]. A similar process occurs also in astronauts to alleviate the “pseudopolycythemia” that ensues over the first days in low gravity, due to a fast redistribution of blood from lower body to thorax and reduction of plasma volume [7,8]. An association between erythrocyte clearance and EPO decrease has been found also in patients affected by renal failure, where impairment of kidney function affects EPO production [9,10], and in healthy human subjects where EPO variations are artificially induced as in blood doping [11].…”

Section: Introductionmentioning

confidence: 99%

Survival and Senescence of Human Young Red Cellsin Vitro

Risso

Ciana

Achilli

et al. 2014

Cell Physiol Biochem

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Background: A number of experimental investigations in vivo suggest that in humans a decrease of circulating erythrocyte number ensues whenever erythropoietin (EPO) plasma level decreases. Since the process seems to selectively eliminate young red cells (neocytes), it has been named neocytolysis. The experimental models in vivo have revealed and documented multiple forms of neocytolysis but have not fully elucidated the specificity of the target red cells and the relation with EPO level changes. In an attempt to better characterize the neocytolytic process, we have undertaken an in vitro investigation on age-ranked human red cells. Methods: By centrifugation on Percoll density gradient we separated the red cells population into three subsets, neocytes, middle-aged and old. Then we comparatively investigated the kinetics of survival of the subsets cultured under different conditions: with medium alone, with 10% autologous plasma, with EPO, alone or in combination with autologous monocytes. Results: Neocytes showed a viability and a survival rate lower than the other red cells when cultured in medium or with 10% plasma. EPO at physiological doses increased their survival rate, but not that of the other subsets. This effect was enhanced by co-culture with monocytes. Conclusion: Likely neocytes are more sensitive than the other RBCs subsets to presence or absence of survival signals, such as EPO or plasma or monocytes derived factors. These observations could provide an insight into the link between the decrease in EPO plasma level and the reduction of circulating red cells mass and account for the specificity of neocytes clearance.

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Modulation of red cell mass by neocytolysis in space and on Earth

Cited by 42 publications

References 11 publications

Intermittent Hypoxic Training: Fact and Fancy

Intermittent Hypoxic Training: Fact and Fancy

The Negative Regulation of Red Cell Mass by Neocytolysis: Physiologic and Pathophysiologic Manifestations

Survival and Senescence of Human Young Red Cellsin Vitro

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