Deposition of Iron in the Bone Marrow of a Murine Model of Hematopoietic Acute Radiation Syndrome

Abstract

Exposure to high-dose total body irradiation (TBI) can result in hematopoietic acute radiation syndrome (H-ARS), characterized by leukopenia, anemia, and coagulopathy. Death from H-ARS occurs from hematopoietic insufficiency and opportunistic infections. Following radiation exposure, red blood cells (RBCs) undergo hemolysis from radiation-induced hemoglobin denaturation, causing the release of iron. Free iron can have multiple detrimental biological effects, including suppression of hematopoiesis. We investigated the impact of radiation-induced iron release on the bone marrow following TBI and the potential impact of the ACE inhibitor captopril, which improves survival from H-ARS. C57BL/6J mice were exposed to 7.9 Gy, 60 Co irradiation, 0.6 Gy/min (LD 70−90/30 ). RBCs and reticulocytes were significantly reduced within 7 days of TBI, with the RBC nadir at 14−21 days. Iron accumulation in the bone marrow correlated with the time course of RBC hemolysis, with an »10-fold increase in bone marrow iron at 14−21 days post-irradiation, primarily within the cytoplasm of macrophages. Iron accumulation in the bone marrow was associated with increased expression of genes for iron binding and transport proteins, including transferrin, transferrin receptor 1, ferroportin, and integrin aMb2. Expression of the gene encoding Nrf2, a transcription factor activated by oxidative stress, also increased at 21 days post-irradiation. Captopril did not alter iron accumulation in the bone marrow or expression of iron storage genes, but did suppress Nrf2 expression. Our study suggests that following TBI, iron is deposited in tissues not normally associated with iron storage, which may be a secondary mechanism of radiation-induced tissue injury. Published by Elsevier Inc. on behalf of ISEH -Society for Hematology and Stem Cells. This is an open access article under the CC BY-NC-ND license.

Multispectral fluorine-19 MRI enables longitudinal and noninvasive monitoring of tumor-associated macrophages

“…Collectively, these results showed that, although MDMs and MG are generally evenly distributed within untreated tumors, at recurrence, we observe the spatial emergence of localized clusters Although these analyses revealed different spatial patterns of TAMs in untreated versus RT-recurrent tumors, it did not enable the temporal discrimination of the sequence of cell infiltration throughout the experimental time course. Given that RT has been reported to lead to hemolysis and hemoglobin release in other contexts (46,47), we assessed whether this process is also evident in gliomas after RT and whether iron uptake by specific cells could thereby mark them in a temporal manner. We therefore stained PDG-Ink4a/Arf KO glioma sections with Prussian blue (PB) to visualize iron deposition.…”

Iron Deposition and Ferroptosis in the Spleen in a Murine Model of Acute Radiation Syndrome

“…Our laboratory and others have demonstrated that radiation-induced hemolysis of RBC is associated with an accumulation of iron in the bone marrow in rodent models of H-ARS [ 27 , 28 ]. The reduction of circulating RBC increased iron in the plasma, and increased iron levels in hemosiderin in the bone marrow have been associated with increased levels of hepcidin expression in the liver following TBI [ 28 , 29 ]. This suggests that iron release from intestinal cells is suppressed in response to high plasma iron following TBI.…”

Iron Deposition and Ferroptosis in the Spleen in a Murine Model of Acute Radiation Syndrome

“…Previous studies from our laboratory have shown that captopril mitigates ARS in mice and in Göttingen minipigs 27,46 . However, our current data indicate that captopril treatment did not mitigate radiationinduced reduction of RBC or HGB, or deposition of iron in the spleen.…”

“…Our laboratory and others have demonstrated that radiation-induced hemolysis of RBC is associated with an accumulation of iron in the bone marrow in rodent models of H-ARS 26,27 . Here we investigated the deposition of iron in the spleen following TBI in mice.…”

“…Sub-lethal irradiation results in iron deposition in the spleen and upregulation of genes encoding iron handling proteins Our laboratory and others demonstrated that following radiation-induced hemolysis, iron is deposited within the bone marrow 27,28 . Iron recycling normally occurs within the spleen, where specialized macrophages take up senescent or damaged RBC 24 .…”