title: Inhibition of intestinal epithelial apoptosis improves survival in a murine model of radiation combined injury.
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.
authors.affiliation: Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Enjae
authors.initials: E
authors.lastname: Jung
authors.forename: Erin E
authors.initials: EE
authors.lastname: Perrone
authors.forename: Pavan
authors.initials: P
authors.lastname: Brahmamdan
authors.forename: Jacquelyn S
authors.initials: JS
authors.lastname: McDonough
authors.forename: Ann M
authors.initials: AM
authors.lastname: Leathersich
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Dominguez
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Clark
authors.forename: Amy C
authors.initials: AC
authors.lastname: Fox
authors.forename: W Michael
authors.initials: WM
authors.lastname: Dunne
authors.forename: Richard S
authors.initials: RS
authors.lastname: Hotchkiss
authors.forename: Craig M
authors.initials: CM
authors.lastname: Coopersmith
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology / Q000382:microbiology / Q000528:radiation effects; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology / Q000382:microbiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000382:microbiology / Q000528:radiation effects; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000382:microbiology / Q000528:radiation effects; D003713:Dendritic Cells / Q000276:immunology / Q000382:microbiology / Q000528:radiation effects; D005720:Gamma Rays; D015870:Gene Expression; D007413:Intestinal Mucosa / Q000276:immunology* / Q000382:microbiology / Q000528:radiation effects; D007694:Killer Cells, Natural / Q000276:immunology / Q000382:microbiology / Q000528:radiation effects; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000528:radiation effects; D055624:Methicillin-Resistant Staphylococcus aureus / Q000254:growth & development / Q000472:pathogenicity; D051379:Mice; D008822:Mice, Transgenic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000276:immunology; D011833:Radiation Injuries, Experimental / Q000150:complications / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D013203:Staphylococcal Infections / Q000150:complications / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D016019:Survival Analysis; D014915:Whole-Body Counting
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2