Exosomes are involved in total body irradiation-induced intestinal injury in mice

• 作者: Hang Li Mian Jiang Shu-ya Zhao Shu-qin Zhang Lu Lu Xin He Guo-xing Feng Xin Wu Sai-jun Fan
• 来源期刊: 中国药理学报（英文版）
• 年，卷（期）: 2021,（7）
• 所属期刊栏目: Gastrointestinal Pharmacology
• 页码范围: 1111-1123
• 页数: 13页
• 语种: 英文

摘要

Ionizing radiation-induced intestinal injury is a catastrophic complication in patients receiving radiotherapy.Circulating exosomes from patients undergoing radiotherapy can mediate communication between cells and facilitate a variety of pathological processes in vivo,but its effects on ionizing radiation-induced intestinal damage are undetermined.In this study we investigated the roles of exosomes during total body irradiation(TBI)-induced intestinal injury in vivo and in vitro.We isolated exosomes from serum of donor mice 24 h after lethal dose(9 Gy)TBI(Exo-IR-24h),then intravenously injected the exosomes into receipt mice,and found that Exo-IR-24h injection not only exacerbated 9 Gy TBI-induced lethality and weight loss,but also promoted crypt-villus structural and functional injury of the small intestine in receipt mice.Moreover,Exo-IR-24h injection significantly enhanced the apoptosis and DNA damage of small intestine in receipt mice following TBI exposure.In murine intestinal epithelial MODE-K cells,treatment with Exo-IR-24h significantly promoted 4 Gy ionizing radiation-induced apoptosis,resulting in decreased cell vitality.We further demonstrated that Exo-IR-24h promoted the IR-induced injury in receipt mice partially through its DNA damage-promoting effects and attenuating Nrf2 antioxidant response in irradiated MODE-K cells.In addition,TBI-related miRNAs and their targets in the exosomes of mice were enriched functionally using Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analyses.Finally,injection of GW4869(an inhibitor of exosome biogenesis and release,1.25 mg·kg-1·d-1,ip,for 5 consecutive days starting 3 days before radiation exposure)was able to rescue mice against 9 Gy TBI-induced lethality and intestinal damage.Collectively,this study reveals that exosomes are involved in TBI-induced intestinal injury in mice and provides a new target to protect patients against irradiation-induced intestinal injury during radiotherapy.