WAG/RijCmcr rat models for injuries to multiple organs by single high dose ionizing radiation: similarities to nonhuman primates (NHP)

Abstract

Purpose: Defined animal models are needed to pursue the FDA Animal Rule for approval of medical countermeasure for radiation injuries. This study compares WAG/RijCmcr rat and nonhuman primate (NHP) models for acute radiation syndrome (ARS) and delayed effects of acute radiation exposure (DEARE).

Materials and methods: Irradiation models include total body irradiation, partial body irradiation with bone marrow sparing and whole thorax lung irradiations. Organ-specific sequelae of radiation injuries were compared using dose–response relationships.

Results and conclusions: Rats and NHP manifest similar organ dysfunctions after radiation, starting with acute gastrointestinal (GI-ARS) and hematopoietic (H-ARS) syndromes followed by lung, heart and kidney toxicities. Humans also manifest these sequelae. Latencies for injury were earlier in rats than in NHP. After whole thorax lung irradiations (WTLI) up to 13 Gy, there was recovery of lung function from pneumonitis in rats. This has not been evaluated in NHP. The latency, incidence, severity and progression of radiation pneumonitis was not influenced by early multi-organ injury from ARS in rats or NHP. Rats developed more severe radiation nephropathy than NHP, and also progressed more rapidly. Dosimetry, anesthesia, environment, supportive care, euthanasia criteria etc., may account for the alterations in radiation sensitivity observed between species.

Keywords:

• Probit
• radiation dose–response relationship
• whole thorax lung irradiation
• partial body irradiation
• bone marrow sparing
• radiation pneumonitis
• radiation nephropathy

Acknowledgements

We acknowledge the idea and encouragement for this paper by Merriline M. Satyamitra (National Institute of Allergy and Infectious Diseases, Bethesda, Maryland). We thank all members of the Medhora and Moulder labs for their invaluable participation, support and efforts. We thank Yvonne Morauski for editing the manuscript. Funding was supported by NIAID U01AI107305, U01AI133594, RC1 AI81294 and U19AI67734 and the Department of Radiation Oncology at the Medical College of Wisconsin. We also acknowledge the continued discussion, insight and constructive critique and funding of our NIAID and BARDA colleagues. The study could not have been performed without the tremendous support and expertise of the research staff of the UMB Preclinical Radiobiology lab and the MCART radiation physics core. Funding was provided by NIAID HHSN272201000046C, SRI/NIAID HHSN272201500013I and BARDA HHS00100201100007C.

Disclosure statement

The authors report no conflicts of interest.

Additional information

Notes on contributors

Brian L. Fish

Brian L. Fish is a normal tissue radiation biologist working with WAG/RijCmcr rats for the past 3 decades. He specializes in radiation injury to normal tissues and mitigation by ACE inhibitors.

Thomas J. MacVittie

Thomas J. MacVittie has demonstrated a consistent record of accomplishment in research and management skills focused on integrating experts of multiple disciplines to achieve common goals. This effort continues with the evolution of our approach to understanding the link between the ARS and DEARE. We are focused on developing a more strategic approach to MCM development and the refinement of animal models for the H-, GI-ARS, lung damage and multi-organ injury to include the heart and kidney.

Aniko Szabo

Aniko Szabo is the Director of the Biostatistics Consulting Service at MCW. She is an expert on statistical modelling of biomedical data. She has worked with the Medhora lab since 2010.

John E. Moulder

John E. Moulder is Professor Emeritus of Radiation Oncology at the Medical College of Wisconsin. His primary research interest is the development of methods to detect, mitigate and treat injuries from medical and accidental radiation exposure. He was one of the first researchers to demonstrate that late tissue injury from radiation exposure could be both treated and mitigated.

Meetha Medhora

Meetha Medhora is a Professor of Radiation Oncology, Pulmonary and Critical Care Medicine and Physiology at MCW. She is a molecular biologist by training but has worked on radiation injury to the lung since 2005 and late effects of radiation to the kidneys and heart since 2012.