The Role of Oxygen in the Regulation of Erythropoiesis. Depression of the Rate of Delivery of New Red Cells to the Blood by High Concentrations of Inspired Oxygen 12

Tinsley, John C.; Moore, Carl V.; Dubach, Reubenia; Minnich, Virginia; Grinstein, Moisés

doi:10.1172/jci102221

Cited by 49 publications

(8 citation statements)

References 18 publications

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“…26 Older studies of transfused SCD patients have revealed an inappropriately low reticulocyte response that was out of proportion with the degree of erythroid hyperplasia, suggesting compromise in the exiting of sickle RBCs from marrow. [27][28][29] Consistent with these observations, Finch et al performed ferrokinetic measurements of erythropoiesis on a continuously transfused woman with severe SCD, which revealed high radioactive iron uptake in the erythroid marrow, of which a disproportionately large quantity was not subsequently released into circulating RBCs. They hypothesized that in the setting of chronic transfusion, intramedullary erythroid maturation would occur relatively slowly and thereby increase the amount of sickle hemoglobin within the marrow, which would result in a mechanical type of ineffective erythropoiesis.…”

Section: Discussionmentioning

confidence: 93%

Evidence for ineffective erythropoiesis in severe sickle cell disease

Krishnamurti

Kutok

et al. 2005

Blood

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IntroductionSickle cell disease (SCD) is a common and severe disorder in which a missense mutation in the ␤-globin gene results in polymerization of hemoglobin S under deoxygenating conditions, leading to chronic peripheral hemolysis and intravascular vaso-occlusion. Less fully appreciated is the extent to which sickle hemoglobin in committed erythroid precursor cells might also affect earlier events in erythropoiesis. Improved understanding of the impact of SCD on intramedullary erythropoiesis is relevant to the development of new therapeutic strategies for this chronic debilitating disease.One approach to directly assess the contribution of ineffective erythropoiesis to the pathophysiology of sickle cell disease is to analyze erythropoiesis in sickle cell disease patients who have undergone matched related donor allogeneic stem cell transplantation (SCT) following a nonmyeloablative (NMA) conditioning regimen. A variety of nonmyeloablative conditioning regimens have been developed to facilitate engraftment of donor stem cells and reduce the treatment-related toxicity of hematopoietic SCT. [1][2][3][4] In this nonmyeloablative setting, host hematopoiesis frequently persists following transplantation and coexists with engrafted donor cells within the marrow. Depending on the underlying disease and the intensity of the conditioning regimen, stable mixed hematopoietic chimerism occurs frequently and can persist for long intervals. Mixed hematopoietic chimerism has been well documented after allogeneic hematopoietic SCT for SCD, and this provides a unique opportunity to perform a direct side-by-side comparison of normal and sickle erythropoiesis in vivo. 5,6 To distinguish between donor and host erythropoiesis, we previously developed methods to specifically measure erythroid lineage chimerism in both nucleated and non-nucleated erythroid elements. Although molecular methods for measurement of donor chimerism are well established, they are based on analysis of genomic DNA, and thus measure nucleated-cell chimerism, which is predominantly leukocyte derived in peripheral blood. 7-9 Therefore, in addition to measuring overall engraftment by analysis of genomic DNA, the present studies also use two alternate methods to distinguish between donor and host-derived erythropoiesis. One method relies on direct enumeration of donor-derived erythroid precursors on paraffin-imbedded marrow sections following staining with a donor-specific marker, such as red blood cell (RBC) isohemagglutinin antigens in an ABO disparate setting. A second method uses a novel molecular assay, RNA ␤-globin pyrosequencing, which directly measures erythroid lineage-specific chimerism from total RNA by quantifying the amount of RBC-specific RNA transcripts that bear a donor or host-specific single nucleotide polymorphism (SNP) or mutation. 6 In addition to using the sickle mutation as an informative ␤-globin SNP, we also previously identified an alternate ␤-globin SNP, 3H3, that occurs at high minor allele frequency. 6 Since ␤-globin RNA is expressed...

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Section: Discussionmentioning

confidence: 93%

Evidence for ineffective erythropoiesis in severe sickle cell disease

Krishnamurti

Kutok

et al. 2005

Blood

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“…In the normal individual the activity of the bone marrow appears to be related to the oxygen capacity of the circulating blood (11,12). By decreasing the circulating level of hemoglobin by phlebotomy, a stimulus is provided for increased hematopoiesis to compensate for the deficiency in oxygen carrying capacity of the blood.…”

Section: Discussionmentioning

confidence: 99%

Iron Metabolism. Hematopoiesis Following Phlebotomy. Iron as a Limiting Factor 1

Finch¹,

Haskins²,

Finch³

1950

J. Clin. Invest.

122

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In the studies to be reported, dogs and men were repeatedly phlebotomized over a period of several months. The bleeding produced anemia and thereby stimulated hematopoiesis. The removed blood contained certain materials necessary for production of blood. It was anticipated that red cell stroma, pyrol pigment, and globin would be fabricated with ease while the assimilation of iron would be more limited. Attention was, therefore, directed toward the iron metabolism of the phlebotomized subjects. In individuals with great variation in body iron stores the degree of anemia produced, the mobilization of body iron and the rate of hematopoiesis were calculated. The results are presented to indicate the role which iron plays in hematopoiesis following the loss of blood. MATERIALS AND METHODSRed cell counts were done with calibrated U. S. Bureau of Standards pipettes in duplicate. Hemoglobin was determined colorimetrically by the method of Evelyn (1).Wintrobe tubes were used for hematocrit determinations.Reticulocyte counts were done by the method of Osgood and Wilhelm (2). Serum iron and iron-binding protein were determined as previously reported (3)

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“…Diminished red blood cell production after prolonged exposure of animals or man to a high oxygen tension results from an alteration of the marrow regulatory system (1)(2)(3). Possible explanations include: a diminislhed production of the erythropoietic hormone, erythropoietin; active suppression of erythropoiesis as suggested by the demonstration of an erythropietin antagonist in the plasma of plethorisc animals by Krzymowski and Przala (4) and by Whitcomb and Moore ( 5 ) , or a diminished marrow productive capacity due to a direct toxic effect of oxygen.…”

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confidence: 99%

Erythropoiesis and Hyperoxia

Fletcher

Gallagher

Warnecke

et al. 1973

Experimental Biology and Medicine

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Diminished red blood cell production after prolonged exposure of animals or man to a high oxygen tension results from an alteration of the marrow regulatory system (1-3). Possible explanations include: a diminislhed production of the erythropoietic hormone, erythropoietin; active suppression of erythropoiesis as suggested by the demonstration of an erythropietin antagonist in the plasma of plethorisc animals by Krzymowski and Przala (4) and by Whitcomb and Moore ( 5 ) , or a diminished marrow productive capacity due to a direct toxic effect of oxygen. In order to explore the mechanisms by which hyperoxia produces a decrease in erythropoiesis, the erythropoietic response and plasma erythropoietin titers of rats exposed to a sustained increase in environmental oxygen were studied. In addition, erythropoiesis was assessed in each partner of parabiotic pairs maintained in such a manner that one partner breathed a normal oxygen environment and the other a hyperoxic environment. The results indica ted ery thropoie t ic suppression following hyperoxic exposure and suggest the production of a humoral erythropoietic antagonist. The latter conclusion is supported by the suppression of erythropoiesis in the parabiotic partner maintained in a normal oxygen environment. These data support the hypothesis that erythropoiesis is regulated by the dynamic interaction of a humoral accelerator of erythropiesis and an erythropoietic inhibitor.Methods and Materials. Hyperoxic experiments. Female Sprague-Dawley rats weighing 180-200 g maintained on a diet of Purina Laboratory Chow and allowed tap water ad libitum were utilized in all experiments. Animals exposed to hyperoxia were maintained in a specially constructed Plexi-glas chamber1 with temperature and humidity control2 and a source of oxygen regulated by an automatic oxygen analyzer3 in order to maintain the oxygen concentration within the chamber at the specified level. The animals were in the chamber continuously except for 30-60 min each day at which time the chamber was serviced and food and water replenished.Six groups of 10 animals each were exposed to a 95-100% oxygen environment for intervals of 24, 48, 72, and 120 hr. Eighteen hr prior to each specified time interval and the termination oi f each experiment, 1 pCi 59Fe per 1 pg 56Fe citrate was administered iv via tail vein. Eighteen hr thereafter, the animals were removed from the chamber, anesthetized with ether, and exsanguinated by cardiac punlcture under direct visualization by means of a preheparinized plastic syringe. The 18-hr RBC radioiron incorporation was determined in a manner previously described (6). Appropriate control groups were maintained at atmospheric conditions under similar temperature and humidity.In a similar fashion, 14 groups of 20 animals each were exposed to 50% oxygen for intervals of 0-20 days. Twenty-four-hr RBC radioiron incorporations were determined at daily intervals on day 0-3, 5-9, 12-16, and on day 20. Appropriate control rats were maintained at atmospheric conditions. In selected gr...

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The Role of Oxygen in the Regulation of Erythropoiesis. Depression of the Rate of Delivery of New Red Cells to the Blood by High Concentrations of Inspired Oxygen 12

Cited by 49 publications

References 18 publications

Evidence for ineffective erythropoiesis in severe sickle cell disease

Evidence for ineffective erythropoiesis in severe sickle cell disease

Iron Metabolism. Hematopoiesis Following Phlebotomy. Iron as a Limiting Factor 1

Erythropoiesis and Hyperoxia

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