caesium-137 and Acute-Radiation-Syndrome

Thrombocytopenia is a major complication in hematopoietic-acute radiation syndrome (H-ARS) that increases the risk of mortality from uncontrolled hemorrhage. There is a great demand for new therapies to improve survival and mitigate bleeding in H-ARS. Thrombopoiesis requires interactions between megakaryocytes (MKs) and endothelial cells. 16, 16-dimethyl prostaglandin E2 (dmPGE2), a longer-acting analogue of PGE2, promotes hematopoietic recovery after total-body irradiation (TBI), and various angiotensin-converting enzyme (ACE) inhibitors mitigate endothelial injury after radiation exposure. Here, we tested a combination therapy of dmPGE2 and lisinopril to mitigate thrombocytopenia in murine models of H-ARS following TBI. After 7.75 Gy TBI, dmPGE2 and lisinopril each increased survival relative to vehicle controls. Importantly, combined dmPGE2 and lisinopril therapy enhanced survival greater than either individual agent. Studies performed after 4 Gy TBI revealed reduced numbers of marrow MKs and circulating platelets. In addition, sublethal TBI induced abnormalities both in MK maturation and in in vitro and in vivo platelet function. dmPGE2, alone and in combination with lisinopril, improved recovery of marrow MKs and peripheral platelets. Finally, sublethal TBI transiently reduced the number of marrow Lin-CD45-CD31+Sca-1- sinusoidal endothelial cells, while combined dmPGE2 and lisinopril treatment, but not single-agent treatment, accelerated their recovery. Taken together, these data support the concept that combined dmPGE2 and lisinopril therapy improves thrombocytopenia and survival by promoting recovery of the MK lineage, as well as the MK niche, in the setting of H-ARS.

Topics: 16,16-Dimethylprostaglandin E2; Acute Radiation Syndrome; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Platelets; Bone Marrow; C-Reactive Protein; Cesium Radioisotopes; Drug Evaluation, Preclinical; Endothelial Cells; Endothelium, Vascular; Female; Gamma Rays; Hemorrhagic Disorders; Lisinopril; Megakaryocytes; Mice; Mice, Inbred C57BL; P-Selectin; Platelet Aggregation; Platelet Factor 4; Radiation Injuries, Experimental; Thrombocytopenia; Thrombopoiesis; von Willebrand Factor; Whole-Body Irradiation

Accidents or radiological attacks may lead to ingestion of Cs by large numbers of the public. This work models the efficacy of Prussian blue, the medical countermeasure for internal contamination with Cs, to prevent acute radiation syndrome as a function of the duration of treatment and the time that treatment starts after uptake. Risk of acute radiation syndrome is modeled using the International Commission on Radiological Protection's acute radiation hazard model. Dose rates to target organs from Cs ingestion were based on the data published by the US Environmental Protection Agency and the retention of Cs in the reference man. Modeling found that treatment is most effective if begun within 15 d of ingestion, and the course length should be at least 75 d to mitigate cancer risk and 290 d to mitigate fatalities due to acute radiation syndrome. Both of these course lengths are much longer than the minimum Prussian blue treatment regimen of 30 d. Extending the treatment time for contaminated individuals would increase demand for Prussian blue following an accident or attack and in turn, would require a larger stockpile of Prussian blue to meet demand. Not enough data is available to determine if this longer treatment time would lead to adverse medical outcomes due to the toxicity of the treatment itself.

Topics: Acute Radiation Syndrome; Adult; Antidotes; Cesium Radioisotopes; Decontamination; Eating; Ferrocyanides; Humans; Male; Phantoms, Imaging; Radiation Exposure; Radiation Injuries; Radiation Protection; Young Adult