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Author Notes:

Correspondence: Craig M. Cooper; smithE-mail: cmcoop3@emory.edu

Conceived and designed the experiments: EJ, RSH and CMC.

Performed the experiments: EJ, EEP, PB, JSM, AML, JAD, ATC, ACF and WMD.

Analyzed the data: EJ, EEP, PB, JSM, AML, JAD, ATC, ACF, WMD, RSH and CMC.

Contributed reagents/ materials/ analysis tools: WMD. Wrote the paper: EJ and CMC.

Disclosures: The authors have declared that no competing interests exist.

Subjects:

Research Funding:

This work was supported by funding from the National Institutes of Health (GM072808, GM66202, GM104323, GM008795, DK52574).

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

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Journal Title:

PLoS ONE

Volume:

Volume 8, Number 10

Publisher:

, Pages e77203-e77203

Type of Work:

Article | Final Publisher PDF

Abstract:

World conditions place large populations at risk from ionizing radiation (IR) from detonation of dirty bombs or nuclear devices. In a subgroup of patients, ionizing radiation exposure would be followed by a secondary infection. The effects of radiation combined injury are potentially more lethal than either insult in isolation. The purpose of this study was to determine mechanisms of mortality and possible therapeutic targets in radiation combined injury. Mice were exposed to IR with 2.5 Gray (Gy) followed four days later by intratracheal methicillin-resistant Staphylococcus aureus (MRSA). While either IR or MRSA alone yielded 100% survival, animals with radiation combined injury had 53% survival (p = 0.01). Compared to IR or MRSA alone, mice with radiation combined injury had increased gut apoptosis, local and systemic bacterial burden, decreased splenic CD4 T cells, CD8 T cells, B cells, NK cells, and dendritic cells, and increased BAL and systemic IL-6 and G-CSF. In contrast, radiation combined injury did not alter lymphocyte apoptosis, pulmonary injury, or intestinal proliferation compared to IR or MRSA alone. In light of the synergistic increase in gut apoptosis following radiation combined injury, transgenic mice that overexpress Bcl-2 in their intestine and wild type mice were subjected to IR followed by MRSA. Bcl-2 mice had decreased gut apoptosis and improved survival compared to WT mice (92% vs. 42%; p<0.01). These data demonstrate that radiation combined injury results in significantly higher mortality than could be predicted based upon either IR or MRSA infection alone, and that preventing gut apoptosis may be a potential therapeutic target.

Copyright information:

© 2013 Jung et al.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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