Combined radiation injury and its impacts on radiation countermeasures and biodosimetry

Abstract

Purpose: Preparedness for medical responses to major radiation accidents and the increasing threat of nuclear warfare worldwide necessitates an understanding of the complexity of combined radiation injury (CI) and identifying drugs to treat CI is inevitably critical. The vital sign and survival after CI were presented. The molecular mechanisms, such as microRNA pathways, NF-κB-iNOS-IL-18 pathway, C3 production, the AKT-MAPK cross-talk, and TLR/MMP increases, underlying CI in relation to organ injury and mortality were analyzed. At present, no FDA-approved drug to protect, mitigate, or treat CI is available. The development of CI-specific medical countermeasures was reviewed. Because of the worsened acute radiation syndrome resulting from CI, diagnostic triage can be problematic. Therefore, biodosimetry and CI are bundled together with the need to establish effective triage methods with CI.

Conclusions: CI mouse model studies at AFRRI are reviewed addressing molecular responses, findings from medical countermeasures, and a proposed plasma proteomic biodosimetry approach based on a panel of radiation-responsive biomarkers (i.e., CD27, Flt-3L, GM-CSF, CD45, IL-12, TPO) negligibly influenced by wounding in an algorithm used for dose predictions is described.

Keywords: Combined radiation injury; acute radiation syndrome; biodosimetry; mechanisms; medical countermeasures; wounding.

Figure 1.

CI increases microRNAs in kidneys of mice exposed to radiation followed by hemorrhage. CD2F1 male mice received 8.75 Gy ⁶⁰Co followed by 20% bleeding (Kiang et al. 2017a). Kidneys were collected on day 1 after CI (N = 6 per group). miR; microRNA. These results show changes reflecting greater than 2-fold changes (either increased or decreased) fold changes compared to the 0 Gy group.

Figure 2.

CI-induced miR-34a increases are not different from RI at early time points. B6D2F1 female mice received 9.5 Gy ⁶⁰Co alone or followed by 15% total body surface area wound trauma (Kiang et al. 2010b). Ileums were collected on days 3, 7, 15 and 30 after RI or CI. No differences between the RI-induced increases in miR-34a and the CI-induced increases in miR-34a were found on days 3, 7, and 15. On day 30, the CI-induced increases were significantly greater than the RI-induced increases (N = 4 per group). *p < .05 vs. respective sham or wound alone; ^p<.05 vs. R-30d using T-Test. miR: microRNA (Kiang et al. 2022 for Materials and Methods). S: Sham; W: 15% total body surface wound; RI: 9.5 Gy; CI: 9.5 Gy + 15% total body surface wound. These results show changes compared to the sham group.

Figure 3.

Comparison of effects of radiation vs CI (radiation plus wounding) on plasma serum amyloid A (SAA) in mouse radiation model. (A) Radiation exposure, (B) CI (radiation plus wounding) exposure. Symbols represent the mean and bar the standard error of the mean. Comparison of radiation vs radiation plus wounding samples showed significant differences using the T-test (p < .05) (Supplementary Table 1).

Figure 4.

Comparison of effects of radiation vs. CI (radiation plus wounding) on plasma Fms-like tyrosine kinase 3 ligands (Flt-3L) in mouse radiation model. (A) Radiation exposure, (B) CI (radiation plus wounding) exposure. Symbols represent the mean and bar the standard error of the mean. Comparison of radiation vs radiation plus wounding samples showed either significant differences using the T-test (p < .05) or were less than ~2-fold different (Supplementary Table 1).

Figure 5.

Comparison of effects of radiation vs. CI (radiation plus wounding) on plasma cluster differentiation 27 (CD27; lymphocyte surface biomarker) in mouse radiation model. Materials and methods as described in Figure 3 legend. (A) Radiation exposure, (B) CI (radiation plus wounding) exposure. Symbols represent the mean and bar the standard error of the mean. Comparison of radiation vs radiation plus wounding samples showed either significant differences using the T-test (p < .05) or were less than ~2-fold different (Supplementary Table 1).

Figure 6.

Effect of CI (radiation plus wounding) on radiation dose prediction accuracy based on an algorithm using a panel (i.e., CD27, Flt-3L, GM-CSF, CD45, IL-12, TPO) of plasma biomarkers negligibly affect by combined radiation and wounding. Mice received 0 and 6 Gy with or without skin wounding. Symbols represent the results from individual animals at the designated time points after irradiation. Time points within the dashed lines meet the established dose prediction accuracy criteria. CD27: cluster differentiation 27; Flt-3L: Fms-like tyrosine kinase 3 ligand; GM-CSF: granulocyte-macrophage-colony stimulating factor; CD45: cluster differentiation 45; IL-12: interleukin 12; TPO: thrombopoietin; N: not injured; I: injured.