Humoral Regulation of Red Cell Production

Erslev, Allan J.

doi:10.1182/blood.v8.4.349.349

Cited by 324 publications

(62 citation statements)

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“…Though slower in onset than its cardiopulmonary counterparts, the development of polycythaemia has been the most widely known feature of acclimatisation since Viault first reported a proliferative effect of high altitude on his own red cell count (Viault, 1890). After years of subsequent conjecture, the existence of a humoral erythropoietic factor was eventually proven in rabbits by transfusing normal animals with plasma from severely anaemic donors (Erslev, 1953), although human Epo was not isolated at sufficient purity to obtain a partial protein sequence until 1977. Hypoxia generates a detectable increase in serum Epo within 90 min (Eckardt et al, 1989).…”

Section: Erythropoietic Response To Hypoxiamentioning

confidence: 99%

The human side of hypoxia‐inducible factor

2008

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SummaryWhen humans are exposed to hypoxia, systemic and intracellular changes operate together to minimise hypoxic injury and restore adequate oxygenation. Emerging evidence indicates that the hypoxia-inducible factor (HIF) family of transcription factors plays a central regulatory role in these homeostatic changes at both the systemic and cellular levels. HIF was discovered through its action as the transcriptional activator of erythropoietin, and has subsequently been found to control intracellular hypoxic responses throughout the body. HIF is primarily regulated by specific prolyl hydroxylase-domain enzymes (PHDs) that initiate its degradation via the von Hippel-Lindau tumour suppressor protein (VHL). The oxygen and iron dependency of PHD activity accounts for regulation of the pathway by both cellular oxygen and iron status. Recent studies conducted in patients with rare genetic diseases have begun to uncover the wider importance of the PHD-VHL-HIF axis in systems-level human biology. These studies indicate that, in addition to regulating erythropoiesis, the system plays an important role in cardiopulmonary regulation. This article reviews our current understanding of the importance of HIF in human systems-level physiology, and is modelled around the classic physiological response to high-altitude hypoxia.Keywords: erythropoietin, erythropoiesis, polycythaemia, iron, oxygen sensing.The human response to hypoxia is characterised by systemic changes in haematopoietic, respiratory, and cardiovascular physiology that combine to restore adequate oxygenation.Uptake and transport of oxygen are initially maximised through an increase in ventilation and cardiac output, while oxygen carriage is subsequently optimised through acceleration of erythropoiesis. The homeostatic drive underlying these systemic effects is similarly evident at the cellular level, where hypoxia is met by a coordinated transcriptional response that seeks to minimise hypoxic injury and redress the oxygen debt. This cellular response is controlled by the hypoxia-inducible factor (HIF) family of transcription factors, a DNA binding complex that was first defined as a regulator of erythropoietin (Epo) gene (EPO) expression but which is now known to be conserved in all animal species, irrespective of the presence of specialised oxygen transfer systems such as the lungs, heart, and blood (Semenza, 2004). Studies at the cellular level indicate that HIF directly or indirectly regulates several hundred genes that serve a great variety of functional pathways including angiogenesis, cell growth, apoptosis, energy metabolism and vasomotor regulation (Semenza, 2004). Recent studies in humans have also demonstrated a major role in systemic responses to hypoxia that extends to each of the principal organ systems upon which cellular oxygen delivery ultimately depends. This article reviews our current understanding of the importance of HIF in human systems-level physiology, and is modelled around the classic physiological response to high-altitude hypoxia. Reade...

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Section: Erythropoietic Response To Hypoxiamentioning

confidence: 99%

The human side of hypoxia‐inducible factor

2008

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“…These patients, in contrast to normal subjects, exhibited a diurnal variation in the level ofimmunoreactive Ep with peak levels occurring at midnight. The only variable measured which correlated with the serum immunoreactive Ep level in subjects with chronic lung disease was the level of carboxyhaemoglobin (P< 0.02).The accepted stimulus for erythropoietin (Ep) production in both man and animals is tissue hypoxia (Reissmann, 1950;Erslev, 1953; Stohlman, 1962). Several physiologic adjustments are made when man is subjected to an hypoxic stress.…”

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confidence: 99%

“…The accepted stimulus for erythropoietin (Ep) production in both man and animals is tissue hypoxia (Reissmann, 1950;Erslev, 1953; Stohlman, 1962). Several physiologic adjustments are made when man is subjected to an hypoxic stress.…”

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confidence: 99%

Diurnal Levels of Immunoreactive Erythropoietin in Normal Subjects and Subjects with Chronic Lung Disease

et al. 1981

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Serum levels of immunoreactive erythropoietin (Ep) were measured in 48 normal male and female volunteers, ages 20-60 years, to establish a control value for Ep of 18.5 +/- 5.0 (mean +/- SD) mU/ml. Levels of the hormone were also measured sequentially over a 24 h period of time in an additional 17 'normal' volunteers with no diurnal variation. Diurnal levels of immunoreactive Ep were also measured in 30 subjects, with chronic lung disease. These patients, in contrast to normal subjects exhibited a diurnal variation in the level of immunoreactive Ep with peak levels occurring at midnight. The only variable measured which correlated with the serum immunoreactive Ep level in subjects with chronic lung disease was the level of carboxyhaemoglobin (P less than 0.02).

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“…At that time Reissmann observed hyperplasia of the erythroid part of the bone marrow in normoxic rats whose parabiotic partner was submitted to hypoxia [I 31. At about the same time Erslev demonstrated a significant reticulocytosis in rabbits infused with large volumes of plasma from anaemic donor animals [14].…”

Section: Introductionmentioning

confidence: 90%