Abstract
Purpose: The risk of large volume single radiation exposure from accidents, malicious activities, or therapeutic hemi-body irradiation is growing. Such exposures cause large-field irradiation or partial-body irradiation (PBI) that can damage the intestine. No medical countermeasures, referred to as radiation mitigators, are available to suppress intestinal radiation damage when administered after radiation exposure. Methods and materials: We investigated the efficacy of geranylgeranyl transferase inhibitors (GGTis), specifically GGTi-2133 (hereafter GGTi), to mitigate intestinal radiation injury in C57BL/6J mice after exposure to 12 or 13 Gy γ-rays with both hind limbs shielded. Starting 24 hours after PBI and every 48 hours thereafter, we administered either vehicle or GGTi via intraperitoneal injection and collected intestinal tissues on days 3.5 or 14 after 12 Gy PBI from male mice and on day 14 after 13 Gy PBI from female mice. Additionally, the effects of GGTi on endothelial cells after fractionated exposure and on primary intestinal organoids after single exposure were assessed. Results: GGTi treatment increased the number of surviving crypts on day 3.5 after PBI in male mice. In addition, in both sexes, GGTi mitigated intestinal structural damage on day 14. Additionally, GGTi mitigated manifestations of PBI-induced intestinal injury including crypt proliferation; a decrease in the number of mucus-secreting cells and mucus secretion; alterations in stem cell markers at mRNA and protein levels; changes in intestinal neutrophil, lymphocyte, and macrophage counts; and alterations in intestinal vascular endothelial cell markers on day 14 after 12 Gy PBI in male mice. Finally, ex vivo mechanistic studies revealed that GGTi prevents suppression of key beneficial molecules in the human primary endothelial cells and upregulates key molecules essential for intestinal homeostasis and maintenance of intestinal stem cells in the murine intestinal organoids following irradiation. Conclusions: Altogether, our study demonstrates that GGTi is a potent mitigating agent against intestinal radiation toxicity by modifying multiple cell types.