Prevention and Mitigation of Acute Death of Mice after Abdominal Irradiation by the Antioxidant N-Acetyl-cysteine (NAC)

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.

Rapid Loss of Bone Mass and Strength in Mice after Abdominal Irradiation

“…Non-abdomen body parts including the skeleton were shielded with a custom-made cerrobend block. We have reported that the shielding efficacy is >97.5% at a targeted single dose of 20 Gy, and the backscattered radiation (approximately 50 cGy) under this shielding plan does not induce detectable changes in bone marrow cell viability and activity ( 25 ).…”

“…The mice were inspected twice a day and body weight was recorded daily for up to 14 days after the completion of irradiation. Radiation was delivered to the abdomen at a dose rate of 1.079 Gy/min (150 kVp and 6.6 mA) using a Faxitron X-ray Generating System (CP-160, Faxitron X-Ray Corp., Wheeling, IL) as described previously ( 25 ). Non-abdomen body parts including the skeleton were shielded with a custom-made cerrobend block.…”

“…The occurrence of abscopal effects has been recorded, however scantly, in various systems from patients to experimental animals, in different types of tissues from cancerous to normal, and in a wide range of forms of life from humans to plants ( 18–24 ). We have previously reported a rapid abscopal suppression of the bone marrow stromal cell population in mice after abdominal irradiation ( 25 ). Bone marrow stroma hosts the progenitors of bone-forming and resorbing cells and regulates the survival and function of these progenitors and their progeny ( 26 ).…”

The redox-sensitive transcription factor Nrf2 regulates murine hematopoietic stem cell survival independently of ROS levels

“…Radiation exposure is known to generate oxidative stress, and treatment with antioxidants can prevent radiation-induced injury. 35 Four months after irradiation, the percentage of CD45.2 peripheral blood cells was significantly decreased in mice transplanted with Nrf2 Ϫ/Ϫ BM compared with Nrf2 ϩ/ϩ BM ( Figure 2E). Therefore, the survival of Nrf2 Ϫ/Ϫ HSPCs is reduced after the induction of oxidative stress both in vitro and in vivo.…”

Early assessment of dosimetric and biological differences of total marrow irradiation versus total body irradiation in rodents

“…Metabolic function of vital organs, as determined by PET scan, may be preserved in TMI mice and could potentially be used as a non-invasive marker, similar to previously reported initiatives to assess organ toxicity by an FDG PET scan [27–30]. Increased recovery of metabolic function after TMI may be a result of the gastrointestinal-protective effect of TMI [31]. These findings indicate significantly less intestinal damage in the TMI mice as compared to the TBI mice.…”