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. 2010 May;173(5):579-89.
doi: 10.1667/RR2030.1.

Prevention and mitigation of acute death of mice after abdominal irradiation by the antioxidant N-acetyl-cysteine (NAC)

Dan Jia  1 , Nathan A Koonce, Robert J Griffin, Cassie Jackson, Peter M Corry
Affiliations

Prevention and mitigation of acute death of mice after abdominal irradiation by the antioxidant N-acetyl-cysteine (NAC)

Dan Jia et al. Radiat Res. 2010 May.

Abstract

Gastrointestinal (GI) injury is a major cause of acute death after total-body exposure to large doses of ionizing radiation, but the cellular and molecular explanations for GI death remain dubious. To address this issue, we developed a murine abdominal irradiation model. Mice were irradiated with a single dose of X rays to the abdomen, treated with daily s.c. injection of N-acetyl-l-cysteine (NAC) or vehicle for 7 days starting either 4 h before or 2 h after irradiation, and monitored for up to 30 days. Separately, mice from each group were assayed 6 days after irradiation for bone marrow reactive oxygen species (ROS), ex vivo colony formation of bone marrow stromal cells, and histological changes in the duodenum. Irradiation of the abdomen caused dose-dependent weight loss and mortality. Radiation-induced acute death was preceded not only by a massive loss of duodenal villi but also, surprisingly, abscopal suppression of stromal cells and elevation of ROS in the nonirradiated bone marrow. NAC diminished these radiation-induced changes and improved 10- and 30-day survival rates to >50% compared with <5% in vehicle-treated controls. Our data establish a central role for abscopal stimulation of bone marrow ROS in acute death in mice after abdominal irradiation.

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Figures

FIG. 1
FIG. 1
Mouse abdominal irradiation model. Radiographs of (panel A) an unshielded 10-week-old male C57BL/6 mouse with an electronic transponder (arrow) implanted subcutaneously in the upper right back and (panel B) the same mouse positioned for abdominal irradiation with the skeleton shielded by an investigator-designed cerrobend block. Radiography was taken using a Kodak In Vivo Fx Optical Imaging System (Carestream Health, Inc., Rochester, NY).
FIG. 2
FIG. 2
Verification of absorbed doses at the abdomen and validation of shielding efficacy. Ten-week-old male C57BL/6 mice under anesthesia were positioned for irradiation. After dosimetry performed using a PTW Farmer Chamber connected to a CNMC Electrometer that was positioned at the approximated mid-abdomen position, absorbed doses of X rays of various targeted doses at multiple body parts of a mouse were measured using the NanoDot dosimeter chips. Panel A: Positioning of the NanoDot dosimeter chips in a mouse exposed to radiation. NanoDot dosimeter chips were placed on the center of the top and bottom surface of the exposed abdomen (Ab) as well as on the top of the shielded left thigh (Th), chest wall (Ch) and spine (Sp) of anesthetized mice. The mouse was then exposed to 12.5–20.0 Gy X rays at a dose rate of 1.079 Gy/min using a Faxitron X-ray Generating System (CP-160, Faxitron X-Ray Corp., Wheeling, IL). Panel B: Comparison of targeted doses and absorbed doses measured on the top surface of the exposed mouse abdomen positioned for irradiation. Bars are the means and standard deviations calculated from readings on five mice, one reading per dose per mouse. Panel C: Absorbed doses measured at various sites of the mouse body positioned for irradiation. Data are the means and standard deviations calculated from readings on two mice with three readings per site per mouse.
FIG. 3
FIG. 3
Weight loss and surviving fraction after abdominal irradiation. Panel A: Postirradiation changes in body weight. Weight loss is expressed as percentage difference from baseline body weight recorded immediately prior to irradiation. Data are the means of the percentage weight changes. Standard deviations of the means, which ranged from 0.2 to 6.7, are omitted from the graph for simplicity. n = 5–13 per dose. Panel B: Surviving fraction at day 10 (n = 5–13).
FIG. 4
FIG. 4
Histology of small intestine after abdominal irradiation. Representative images from three mice per group; two or three slides per mouse are shown. Scale bar: 0.2 mm.
FIG. 5
FIG. 5
Peripheral white blood cell counts (panel A), ex vivo bone marrow stromal colony formation (panel B), and bone marrow ROS measurements (panel C) 6 days after abdominal irradiation. ROS measurements were normalized to cell number and expressed as percentages of the levels in the controls. Data are means and standard deviations. *P < 0.001 (n = 10–12); **P < 0.01 (n = 3); ***P < 0.01 (n = 8).
FIG. 6
FIG. 6
Effects of NAC treatment on bone marrow ROS levels, ex vivo stromal colony formation and duodenum histology in mice exposed to abdominal irradiation. ROS levels (panel A) and ex vivo fibroblast colony-forming unit formation (panel B) in bone marrow were quantified as described in the Materials and Methods. ROS measurements were normalized to cell numbers and expressed as percentage of the levels in the controls. Data are means and standard deviations (n = 3–4 mice per group). *P <0.01 compared to 0 Gy, **P <0.05 compared to 20 Gy + veh. Panel C: Histological features of duodenum 6 days after abdominal irradiation. Photographs are representative of images from three or four mice per group, two or three slides per mouse. Scale bar: 0.2 mm.
FIG. 7
FIG. 7
Effects of NAC treatment on body weight and survival after abdominal irradiation. Panel A: Postirradiation changes in body weight. Data are the means of the percentage change in body weight from the baseline. Standard deviations of the means, which ranged from 0.9 to 6.7, are omitted from the graph for simplicity (n = 16–41). Panel B: Postirradiation surviving fractions. Calculated from data pooled from five experiments (n = 16–41).
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