Murine hematopoietic-acute radiation syndrome (H-ARS) survivors of total body radiation (TBI) have a significant loss of heart vessel endothelial cells, along with increased tissue iron, as early as 4 months post-TBI. The goal of the current study was to determine the possible role for excess tissue iron in the loss of coronary artery endothelial cells. Experiments utilized the H-ARS mouse model with gamma radiation exposure of 853 cGy (LD50/30) and time points from 1 to 12 weeks post-TBI. Serum iron was elevated at 1 week post-TBI, peaked at 2 weeks, and returned to nonirradiated control values by 4 weeks post-TBI. A similar trend was seen for transferrin saturation, and both results correlated inversely with red blood cell number. Perls' Prussian Blue staining used to detect iron deposition in heart tissue sections showed myocardial iron was present as early as 2 weeks following irradiation. Pretreatment of mice with the iron chelator deferiprone decreased tissue iron, but not serum iron, at 2 weeks. Coronary artery endothelial cell density was significantly decreased as early as two weeks vs. non-irradiated controls (P<0.05), and the reduced density persisted to 12 weeks after irradiation. Deferiprone treatment of irradiated mice prevented the decrease in endothelial cell density at 2 and 4 weeks post-TBI compared to irradiated, nontreated mice (P<0.03). Taken together, the results suggest excess tissue iron contributes to endothelial cell loss early following TBI and may be a significant event impacting the development of delayed effects of acute radiation exposure.
Survivors of acute radiation exposure suffer from the delayed effects of acute radiation exposure (DEARE), a chronic condition affecting multiple organs, including lung, kidney, heart, gastrointestinal tract, eyes, and brain, and often causing cancer. While effective medical countermeasures (MCM) for the hematopoietic-acute radiation syndrome (H-ARS) have been identified and approved by the FDA, development of MCM for DEARE has not yet been successful. We previously documented residual bone marrow damage (RBMD) and progressive renal and cardiovascular DEARE in murine survivors of H-ARS, and significant survival efficacy of 16,16-dimethyl prostaglandin E2 (dmPGE2) given as a radioprotectant or radiomitigator for H-ARS. We now describe additional DEARE (physiological and neural function, progressive fur graying, ocular inflammation, and malignancy) developing after sub-threshold doses in our H-ARS model, and detailed analysis of the effects of dmPGE2 administered before (PGE-pre) or after (PGE-post) lethal total-body irradiation (TBI) on these DEARE. Administration of PGE-pre normalized the twofold reduction of white blood cells (WBC) and lymphocytes seen in vehicle-treated survivors (Veh), and increased the number of bone marrow (BM) cells, splenocytes, thymocytes, and phenotypically defined hematopoietic progenitor cells (HPC) and hematopoietic stem cells (HSC) to levels equivalent to those in non-irradiated age-matched controls. PGE-pre significantly protected HPC colony formation ex vivo by >twofold, long term-HSC in vivo engraftment potential up to ninefold, and significantly blunted TBI-induced myeloid skewing. Secondary transplantation documented continued production of LT-HSC with normal lineage differentiation. PGE-pre reduced development of DEARE cardiovascular pathologies and renal damage; prevented coronary artery rarefication, blunted progressive loss of coronary artery endothelia, reduced inflammation and coronary early senescence, and blunted radiation-induced increase in blood urea nitrogen (BUN). Ocular monocytes were significantly lower in PGE-pre mice, as was TBI-induced fur graying. Increased body weight and decreased frailty in male mice, and reduced incidence of thymic lymphoma were documented in PGE-pre mice. In assays measuring behavioral and cognitive functions, PGE-pre reduced anxiety in females, significantly blunted shock flinch response, and increased exploratory behavior in males. No effect of TBI was observed on memory in any group. PGE-post, despite significantly increasing 30-day survival in H-ARS and WBC and hematopoietic recovery, was not effective in reducing TBI-induced RBMD or any other DEARE. In summary, dmPGE2 administered as an H-ARS MCM before lethal TBI significantly increased 30-day survival and ameliorated RBMD and multi-organ and cognitive/behavioral DEARE to at least 12 months after TBI, whereas given after TBI, dmPGE2 enhances survival from H-ARS but has little impact on RBMD or other DEARE.
The threat of radiation exposure from terrorist activity, warfare, or accidents creates an urgent need to develop agents to mitigate the acute and chronic effects of high dose rate total body irradiation (TBI). High level short‐term radiation exposure results in rapid organ injury leading to development of the acute radiation syndrome (ARS), which if untreated will result in death within weeks. Survivors of ARS will experience the delayed effects of acute radiation exposure (DEARE), which include development of chronic pathology and dysfunction of multiple organ systems months to years following exposure. However, the factors and mechanisms that regulate the onset and progression of cardiovascular DEARE are unclear. The goal of the current study was to determine the possible role for abnormal iron metabolism in the development of cardiac DEARE, especially vascular pathology. Studies utilized the ARS mouse model with gamma radiation exposure at 853 cGy (LD50) and time points from 1 day to 4 months post‐TBI.Serum iron was elevated at 1 day post‐TBI, peaked at 2 weeks, and returned to non‐irradiated control values by 4 weeks post‐TBI. A similar trend was seen for transferrin saturation, and both results correlated inversely with red blood cell number, hematocrit, and hemoglobin concentrations. Perls' Prussian Blue staining was used to detect iron (hemosiderin) deposition in heart paraffin‐embedded tissue sections, and myocardial iron was present as early as 2 weeks post‐TBI. Pretreatment of mice with the iron chelator deferiprone in drinking water decreased myocardial iron deposition (P=0.055), but not serum iron, at 2 weeks. A histological assessment of coronary artery endothelial cell (EC) density showed intimal nuclei per unit area significantly decreased as early as two weeks post‐TBI vs. non‐irradiated controls (P<0.05), and the decrease persisted to 4 months post‐TBI. EC density in deferiprone‐treated mice was significantly increased at 2 and 4 weeks post‐TBI compared to irradiated non‐treated mice (P<0.03). Administration of the ferroptosis inhibitor ferrostatin‐1 via daily i.p. injection for 2 weeks post‐TBI resulted in no change in coronary artery EC density compared to vehicle controls. Taken together, the results suggest the presence of tissue iron contributes to endothelial cell loss occurring early following TBI and is a significant event impacting the development of DEARE. This information may facilitate development of novel medical countermeasures to prevent or mitigate cardiovascular DEARE‐related pathophysiology.Support or Funding InformationNIH 1U01AI107340‐01 (C. Orschell), IUPUI Research Support Funds Grant (S. Miller)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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