Erythropoiesis and Hyperoxia

Abstract

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...

Long‐term intermittent hyperoxic exposures do not enhance erythropoiesis

“…Keramidas et al [7] observed that a 2-h exposure to normobaric hyperoxia did not increase the production of [EPO] in healthy men during a single-blinded counter-balanced crossover investigation. On the contrary, the increased O 2 tension suppressed plasma [EPO] 3-5 h after the breathing intervention, confirming similar previous findings [5,6,8,9]. Thereafter, the plasma [EPO] levels appeared to resume their natural circadian rhythm [12,13].…”

“…This theory conflicts with the reported O 2 -induced erythropoietic suppression in animals [5,6] and humans [7][8][9][10][11]. Keramidas et al [7] observed that a 2-h exposure to normobaric hyperoxia did not increase the production of [EPO] in healthy men during a single-blinded counter-balanced crossover investigation.…”

Acute normobaric hyperoxia transiently attenuates plasma erythropoietin concentration in healthy males: evidence against the ‘normobaric oxygen paradox’ theory

“…In contrast, an erythropoietic suppression following hyperoxic exposure in animals (Fletcher et al. 1973, Morshchakova et al.…”

Enhanced Hypoxia-stimulated Erythropoietin Production in Mice with Depression of Erythropoiesis Induced by Hyperoxia

“…The drug per se could have altered EPO production independently of its wellknown inhibitory effect on erythropoiesis. Therefore, the present study was designed to further test the modulatory hypothesis of EPO secretion by estimating both plasma EPO titer (during stimulation of hormone production by exposure to hypobaric air) and plasma EPO half-life in a mouse model of functional depressed erythropoiesis induced by exposure to normobaric hyperoxia (Fletcher et al, 1973;Kaplan et al, 1977). The normal response to exogenous EPO observed by Linman and Pierre (1968) in hyperoxic mice was taken as evidence that the lowering effect of hyperoxia on erythropoiesis is mediated by the humoral regulatory mechanism and not by alterations in the erythroid responsiveness to EPO.…”

“…(1968) and Fletcher et al (1973). They demonstrated that the increment in the oxygen content of the blood, by increasing the amount of the gas that is carried in physical solution, effectively depresses red cell production.…”