Abstract
Accidental exposure to ionizing radiation may lead to delayed effects of acute radiation exposure (DEARE) in many organ systems. Activated protein C (APC) is a known mitigator of the acute radiation syndrome. To examine the role of APC in DEARE, we used a transgenic mouse model with 2- to 3-fold increased plasma levels of APC (high in APC, APCHi). Male and female APCHi mice and wild-type littermates were exposed to 9.5 Gy γ-rays with their hind-legs (bone marrow) shielded from radiation to allow long-term survival. At 3 and 6 months after irradiation, cardiac function was measured with ultrasonography. At 3 months, radiation increased cardiac dimensions in APCHi males, while decreases were seen in wild-type females. At this early time point, APCHi mice of both sexes were more susceptible to radiation-induced changes in systolic function compared to wild-types. At 6 months, a decrease in systolic function was mainly seen in male mice of both genotypes. At 6 months, specimens of heart, small intestine and dorsal skin were collected for tissue analysis. Female APCHi mice showed the most severe radiation-induced deposition of cardiac collagens but were protected against a radiation-induced loss of microvascular density. Both male and female APCHi mice were protected against a radiation induced upregulation of toll-like receptor 4 in the heart, but this did not translate into a clear protection against immune cell infiltration. In the small intestine, the APCHi genotype had no effect on an increase in the number of myeloperoxidase positive cells (seen mostly in females) or an increase in the expression of T-cell marker CD2 (males). Lastly, both male and female APCHi mice were protected against radiation-induced epidermal thickening and increase in 3-nitrotyrosine positive keratinocytes. In conclusion, prolonged high levels of APC in a transgenic mouse model had little effects on indicators of DEARE in the heart, small intestine and skin, with some differential effects in male compared to female mice.
Highlights
Military personnel, nuclear facility workers and the general population continue to be at risk for exposure to ionizing radiation due to a radiological event or incident
Total or partial body exposures to ionizing radiation can lead to the acute radiation syndrome (ARS), the outcome of which is mainly determined by bone marrow failure and injuries in the gastrointestinal tract
Only a small number of such radiation mitigators have been approved by the FDA: human recombinant granulocyte colony–stimulating factors (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), sargramostim (Leukine), and the thrombopoietin analog romiplastin (Nplate) [7,8,9]
Summary
Nuclear facility workers and the general population continue to be at risk for exposure to ionizing radiation due to a radiological event or incident. Total or partial body exposures to ionizing radiation can lead to the acute radiation syndrome (ARS), the outcome of which is mainly determined by bone marrow failure and injuries in the gastrointestinal tract. As radiological events are unpredictable and may involve a large number of victims, radiation mitigators are needed to reduce both acute and delayed radiation toxicity when administered 24 hours after exposure. There are no FDA approved countermeasures against gastrointestinal radiation injury or DEARE in various organ systems. Research is needed to provide insight into the mechanisms by which ionizing radiation causes prolonged radiation injuries. Once identified, such mechanisms could reveal additional pathways to be targeted by radiation mitigators
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