Immune System Phenotyping of Radiation and Radiation Combined Injury in Outbred Mice

Abstract

The complexity of a radionuclear event would be immense due to varying levels of radiation exposures and injuries caused by blast-associated trauma. With this scenario in mind, we developed a mouse model to mimic as closely as possible the potential consequences of radiation injury and radiation combined injury (RCI) on survival, immune system phenotype, and immune function. Using a mouse burn injury model and a 137CsCl source irradiator to induce injuries, we report that the immunological response to radiation combined injury differs significantly from radiation or burn injury alone. Mice that underwent radiation combined injury showed lower injury survival and cecal ligation and puncture (CLP) induced polymicrobial sepsis survival rates than mice with single injuries. As anticipated, radiation exposure caused dose-dependent losses of immune cell subsets. We found B and T cells to be more radiation sensitive, while macrophages, dendritic cells and NK cells were relatively more resistant. However, radiation and radiation combined injury did induce significant increases in the percentages of CD4+ regulatory T cells (Tregs) and a subset of macrophages that express cell-surface GR-1 (GR-1+ macrophages). Immune system phenotyping analysis indicated that spleen cells from radiation combined injury mice produced higher levels of proinflammatory cytokines than cells from mice with radiation or burn injury alone, especially at lower dose radiation exposure levels. Interestingly, this enhanced proinflammatory phenotype induced by radiation combined injury persisted for at least 28 days after injury. In total, our data provide baseline information on differences in immune phenotype and function between radiation injury and radiation combined injury in mice. The establishment of this animal model will aid in future testing for therapeutic strategies to mitigate the immune and pathophysiological consequences of radionuclear events.

Inhibition of Intestinal Epithelial Apoptosis Improves Survival in a Murine Model of Radiation Combined Injury

“…In contrast, mortality was markedly increased in IR/MRSA mice, consistent with radiation combined injury models by other groups using burn, trauma, gram negative bacteria or enteric contents as the second injury [5]–[9]. To determine possible mechanisms of mortality, we performed a thorough analysis comparing NR/sham, IR/sham, NR/MRSA and IR/MRSA mice to be able to delineate which abnormalities observed were due to IR alone, MRSA alone, or a synergistic effect seen with radiation combined injury.…”

“…These concurrent injuries, defined as “radiation combined injuries” often worsen morbidity and mortality in animal models [5]–[9]. In addition to concurrent injuries, patients exposed to IR would also be at increased risk for developing infections due to increased host susceptibility to systemic infections from both endogenous and exogenous organisms [10], [11].…”

“…The few studies performed on radiation combined injury involving infection as the second insult have used common gram negative organisms such as Klebsiella pneumoniae or enteric contents using cecal ligation and puncture [4], [5], [12], [13] However, a recent National Institutes of Health consensus meeting explicitly stated that staphylococcal infections should be anticipated in the wake of a radiation event and recommended further study of IR followed by this common gram positive organism [14]. While staphylococcal infections can be sensitive or resistant to methicillin, the incidence of methicillin-resistant Staphylococcus aureus (MRSA) is becoming increasingly common [15].…”

Gamma Delta T Cells Regulate Wound Myeloid CELL Activity After Burn

“…Further characterization of myeloid cells demonstrated that these cells were comprised of both traditional macrophages CD11b + F4/80 + ), as well as CD11b + Gr1 + myeloid cells. These myeloid cells have been shown to increase in animal models and patients with cancer, injury and infection (5, 17, 26, 27). Cairns et al have also shown an accumulation in the periphery of CD11b + F4/80 + macrophages after burn injury (28).…”

Regulatory T Cells Promote β-Catenin–Mediated Epithelium-to-Mesenchyme Transition During Radiation-Induced Pulmonary Fibrosis

“…Disturbances in immunity have been regarded as driving forces in radiation-induced pulmonary fibrosis (11). As a subset of CD4 þ T lymphocytes, regulatory T cells (Tregs) express the surface marker CD25 as well as the transcription factor Fox head box protein 3 (Foxp3), and they play a crucial role in the maintenance of immune-system homeostasis in the airways (12).…”