Storage Iron Kinetics. VII. A BIOLOGIC MODEL FOR RETICULOENDOTHELIAL IRON TRANSPORT

Abstract

A B S T R A C T The processing of erythrocyte iron by the reticuloendothelial cell has been characterized by kinetic measurements of blood radioactivity made after the intravenous injection of heat-damaged erythrocytes labeled with 'Fe and of transferrin-bound 'Fe. The early reticuloendothelial release of iron, a matter of hours, was calculated from the plasma turnover rate of "'Fe and the plasma reappearance of '"Fe. Late release was calculated from the ratio of the cumulative incorporation of both tracers into the circulating red cell mass over a period of 2 wk. There was an initial processing period within the reticuloendothelial cell, after which radioiron either rapidly returned to circulation (ti 34 min) or was transferred to a slowly exchanging pool of storage iron within the reticuloendothelial cell (ti release to plasma of 7 days). These pathways were of equal magnitude in the normal dog. Reticuloendothelial release of iron was largely independent of the pre-existing plasma iron level or transferrin saturation. Diurnal fluctuations in the plasma iron level were shown to be the result of a variable partitioning of iron between the early and late release phases. Acute inflammation resulted in a prompt and marked increase in the fraction of iron stored (late phase), whereas depletion of iron stores resulted in a marked increase in early release.

The binding of human lactoferrin to mouse peritoneal cells.

“…There it takes the iron released from these cells and immediately the FeLf complex is reintroduced into the RES where it accumulates in the form of ferritin, as will be described elsewhere. This storage could correspond to the slow pathway described by Fillet et al (28).…”

“…There is apparently a blockade in the release of iron from the RES. Fillet et al (28) have shown that, in dogs, after the catabolism of hemoglobin in the RES, the iron returns to the plasma via two pathways, one very fast (tl/2, 24 min) and the other very slow (tl/2, 7 days). These pathways are of equal magnitude in normal animals, while in an acute inflammatory reaction there is a marked increase in the proportion of iron processed through the slow pathway.…”

Targeted gene disruption reveals an essential role for ceruloplasmin in cellular iron efflux

“…To examine this hypothesis, serum iron concentrations were measured in Cp ϩ/ϩ and Cp Ϫ/Ϫ mice after the infusion of heatdamaged red blood cells. Under these circumstances, the excess iron derived from the infused red blood cells is rapidly released from the reticuloendothelial system into the plasma (23,24). To eliminate the possibility that excess iron stores in Cp Ϫ/Ϫ mice might affect these results, mice were chosen for these experiments at an age before the onset of detectable differences in tissue iron stores.…”

“…Red cells were obtained after centrifugation at 8,000 ϫ g for 5 min, damaged by heating in PBS, pH 7.4, at 52°C for 30 min, and washed extensively in PBS, pH 7.4. Cp ϩ/ϩ and Cp Ϫ/Ϫ mice were injected via tail vein with a volume of heat-damaged red blood cells to deliver 2 g of iron per g of mouse (23). Serum iron was determined as described above.…”

Acute Phase Proteins: Ferritin and Ferritin Isoforms

“…The increase in ferritin expression by the macrophage mostly influences the early phase of iron release. In normal conditions two-thirds of the iron entering the macrophage/reticuloendothelial system (RES) is released during this phase, but an increase in ferritin expression can result in a decrease in the release of iron during this phase to only 10% of the iron entering the macrophage/RES (Fillet et al, 1974;Torrance et al, 1978). However, the slow release phase of iron from the macrophage is also influenced and can result in a situation where 33% of the iron is still present in storage form in the macrophage/RES after 60 days (Noyes et al, 1960).…”