Abstract
The increasing potential for accidental radiation exposure from either nuclear accidents or terrorist activities has escalated the need for radiation countermeasure development. We previously showed that a 30-day course of high-dose captopril, an ACE inhibitor, initiated 1–4 h after total body irradiation (TBI), improved Hematopoietic Acute Radiation Syndrome (H-ARS) and increased survival in mice. However, because of the time likely required for the deployment of a stockpiled radiation countermeasure to a radiation mass casualty site, there is a need for therapies that can be administered 24–48 hours after initial exposure. Using C57BL/6 mice exposed to an LD50-80/30 of 60Co TBI (7.75–7.9 Gy, 0.615 Gy/min), we show that low-dose captopril administration, initiated as late as 48 h post-TBI and continued for 14 days, significantly enhanced overall survival similarly to high-dose, rapid administration. Captopril treatment did not affect radiation-induced cell cycle arrest genes or the immediate loss of hematopoietic precursors. Reduced mortality was associated with the recovery of bone marrow cellularity and mature blood cell recovery at 21–30 days post-irradiation. Captopril reduced radiation-induced cytokines EPO, G-CSF, and SAA in the plasma. Finally, delayed captopril administration mitigated brain micro-hemorrhage at 21 days post-irradiation. These data indicate that low dose captopril administered as late as 48 h post-TBI for only two weeks improves survival that is associated with hematopoietic recovery and reduced inflammatory response. These data suggest that captopril may be an ideal countermeasure to mitigate H-ARS following accidental radiation exposure.
Highlights
The hematopoietic system is uniquely sensitive to radiation damage, including the mature blood cells and hematopoietic stem cells in the bone marrow compartment that are critical for blood cell regeneration[5,6]
We previously demonstrated that captopril (110 mg/kg/day) allowed 100% survival from an LD50/30 dose of radiation in mice when administered from 1–4 h following radiation exposure through 30 days post-irradiation[16]
We investigated the effect of delayed administration of 110 mg/kg/ day captopril on the survival of mice exposed to 7.5 Gy total body irradiation (TBI) and found that delaying the initial dose of captopril up to 24 h post-TBI was protective from radiation-induced death (Fig. 1A)
Summary
The hematopoietic system is uniquely sensitive to radiation damage, including the mature blood cells and hematopoietic stem cells in the bone marrow compartment that are critical for blood cell regeneration[5,6]. Proliferative rates, rapidly cycling cells display increased DNA damage from radiation, resulting in higher levels of apoptosis and/or senescence[6,11,12]. We previously demonstrated that captopril (110 mg/kg/day) allowed 100% survival from an LD50/30 dose of radiation in mice when administered from 1–4 h following radiation exposure through 30 days post-irradiation[16]. We demonstrated that at the LD50/30 dose of radiation, captopril improved bone marrow and blood cell recovery, including red blood cells, reticulocytes, and platelets. We found that 13 mg/kg/day captopril administered from 48 h through 2 weeks post-irradiation mitigated radiation H-ARS, as characterized by bone marrow repopulation and mature blood cell recovery. Captopril mitigated radiation-induced surges in cytokine expression and reduced vascular dysfunction following ionizing radiation exposure
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