1,4-Dithiothreitol treatment ameliorates hematopoietic and intestinal injury in irradiated mice: Potential application of a treatment for acute radiation syndrome

摘要

Radiation exposure poses a significant threat to public health, which can lead to acute hematopoietic system and intestinal system injuries due to their higher radiation sensitivity. Hence, antioxidants and thiol-reducing agents could have a potential protective effect against this complication. The dithiol compound 1,4-dithiothreitol (DTT) has been used in biochemistry, peptide/protein chemistry and clinical medicine. However, the effect of DTT on ionizing radiation (IR)-induced hematopoietic injury and intestinal injury are unknown. The current investigation was designed to evaluate the effect of DTT as a safe and clinically applicable thiol-radioprotector in irradiated mice. DTT treatment improved the survival of irradiated mice and ameliorated whole body irradiation (WBI)-induced hematopoietic injury by attenuating myelosuppression and myeloid skewing, increasing self-renewal and differentiation of hematopoietic progenitor cells/hematopoietic stem cells (HPCs/HSCs). In addition, DTT treatment protected mice from abdominal irradiation (ABI)-induced changes in crypt-villus structures and function. Furthermore, treatment with DTT significantly enhanced the ABI-induced reduction in Olfm4 positive cells and offspring cells of Lgr5(+) stem cells, including lysozyme(+) Paneth cells and Ki67(+) cells. Moreover, IR-induced DNA strand break damage, and the expression of proapoptotic-p53, Bax, Bak protein and antiapoptotic-Bcl-2 protein were reversed in DTT treated mice, and DTT also promoted small intestine repair after radiation exposure via the p53 intrinsic apoptotic pathway. In general, these results demonstrated the potential of DTT for protection against hematopoietic injury and intestinal injury after radiation exposure, suggesting DTT as a novel effective agent for radioprotection.