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
• wounding
• medical countermeasures
• mechanisms
• acute radiation syndrome
• biodosimetry

Acknowledgements

G. Sigal (MSD Technologies) contributed to the experimental design, analysis of proteomic biomarkers, and dose-prediction algorithm development. Author (JGK) thanks all scientists, technicians, and research assistants for their contributions to the combined radiation injury field over all these years. Author (WFB) wishes to credit the efforts of AFRRI contributors Dr. V Nagy, Dr. NI Ossetrova, K Krasnopolsky, KP Hieber, DP Condiffe, and DJ Sandgren, who contributed to support radiation dosimetry and the proteomic biodosimetry study involving comparison of radiation with combined radiation injury (wounding).

Dedication

Professor John Edward Moulder (1945–2022) scientific contributions spanned a wide-range of interests in radiobiology research and clinical radiotherapy. His contributions also extended into the area of medical readiness to provide radiation diagnosis to triage and guide medical management of potential radiation-exposed individuals with a focus on assessment and medical management of radiation injury to the kidney. We dedicate our manuscript to honor the rich contributions and guidance Professor Moulder provided in this area. He will be truly missed.

Disclosure statement

The authors report no financial conflicts of interest. The manuscript was cleared for publication by the Armed Forces Radiobiology Research Institute, The Uniformed Services of the Health Sciences. The views, opinions, and findings contained in this report are those of the authors and do not reflect official policy or positions of the Armed Forces Radiobiology Research Institute, the Uniformed Services University of the Health Sciences, the Department of Defense, or the United States government.

Data availability statement

Data presented in this review are available in it.

Additional information

Funding

The studies were supported by NIAID-AFRRI Inter-Agency Agreement YI-AI-5045-04, NIAID R21/R33 AI080553, JPC-7 VP000276-01, SAPO: G17070 (a subaward of 5U19AI067773-18) and AFRRI intramural RAB32164, 33336, 33529, 310934, AFR-B2-12950 and AFR-B2-12812 (to JGK). Project funded by Biomedical Advanced Research and Development Authority BARDA (BAA-BARDA-09-36), which is part of the Office of the Assistant Secretary for Preparedness and Response within the US Department of Health and Services. AFRRI’s contributions were part of a sub-award to Drs. NI Ossetrova and WF Blakely. This study was also funded by National Institute of Allergy and Infectious Diseases, National Institute of Allergy and Infectious Diseases, and U.S. Department of Defense.

Notes on contributors

Juliann G. Kiang

Juliann G. Kiang is Principal Investigator of the Armed Forces Radiobiology Research Institute, Professor (Adjunct) of the Department of Pharmacology and Molecular Therapeutics, and Professor (adjunct) of the Department of Medicine, the Uniformed Services University of the Health Sciences, the US Department of Defense.

William F. Blakely

William F. Blakely is a Senior Scientist in the Armed Forces Radiobiology Research Institute (AFRRI), a component of the Uniformed Services University of the Health Sciences (USUHS), and an Assistant Professor in the Preventive Medicine and Biometrics Department, USUHS.