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

Abstract

Current evidence suggests that a modulatory action on O(2)-dependent EPO secretion is exerted by the erythroid/precursor cell population in the erythropoietic organs through a negative feedback system. The hypothesis is based on studies of stimulated-EPO secretion performed in mice in whom the erythropoietic rates were either enhanced or depressed in the presence of normal plasma EPO half-lives. Since erythropoietic depression was elicited by cyclophosphamide administration, which could have altered EPO production directly, the aim of the present investigation was to estimate hypoxia-stimulated EPO secretion in a mouse model of functional depressed erythropoiesis induced by exposure to normobaric hyperoxia. Females CF#1 mice aged 70 d were divided into control (C) and experimental (E) groups. The former was maintained in plastic cages in a normal environment, while the latter was placed in an environment of 60% O(2)/40% N(2) in an 85-dm(3) atmospheric chamber with air flow of 1 L/min. Erythropoiesis was evaluated by either 24-h RBC-(59)Fe uptake or iron kinetics performed 3 h after IV injection of a tracer dose of (59)Fe. Both indexes of the red cell production rate were significantly depressed in E mice. Plasma disappearance of exogenous EPO in C mice, as well as in E mice exposed to hyperoxia for 4 d, was estimated by injecting (125)I-rHuEPO intravenously. Linear regression analysis indicated that neither the differences between the slopes of both curves nor the Y-intercepts were significant. Hypobaric hypoxemia was used as stimulus for EPO production. Plasma immuno-EPO titer after a 4-h exposure to hypobaric air was 73% higher in mice with hyperoxia-induced hypoerythropoiesis than in control mice with normal erythropoiesis. Data support the concept that the rate of erythropoiesis, perhaps through the number of the erythroid progenitor/precursor cell population, modulates O(2)-dependent EPO secretion.

Changes in erythropoietin and haemoglobin concentrations in response to saturation diving

“…EPO is present in plasma and necessary for maintaining the cells viability (Spivak et al 1991). Renal tissue hypoxia is the principal stimulus for EPO production both in man (Eckard et al 1989, Milledge and Cotes 1985, Klausen et al 1996 and animals (Bozzini et al 2003). In contrast, there are several known mechanisms for its downregulation including blood transfusion (Walle et al 1987), increased blood viscosity (Singh et al 1993), increased EPO catabolism (McMahon et al 1990), and increased cytokin production associated with infections, inflammations and cancer (Means and Krantz 1992).…”

Erythropoietin elevates but not voluntary wheel running in mice

“…Second, regulatory mechanisms (e.g. blood P O2 ) were negatively feeding back onto the erythropoietin process, dampening further red blood cell production (Krantz, 1991;Bozzini et al, 2003). Third, erythrocyte production did rise in a dose-dependent manner but the spleen was storing the additional erythrocytes; thus, regulating blood [Hb] at a constant level.…”