基于p53-TLRs通路的中药防治急性辐射损伤的效应及机制研究

Acute radiation injury is an important factor, which affects the working and fighting capacities of navy, and even threatens their life safety. However, most of the current radiation protectors are single active, or low effective, or highly toxic. Traditional Chinese herbs have the advantage of overall regulation. Moreover, they are quite effective, less or non-toxic, abundant in natural resources, and cheap. Therefore, to develop an economical, efficient, and non-toxic radiation protective Chinese medicine, is an emergent necessary for navy soldiers to protect their health, to avoid radiation injury, and to increase combat effectiveness. Yet, to develop a symptomatic radiation protective Chinese medicine, we must first make clear some key scientific problems such as the mechanisms of radiation injury, and the effective mechanisms of Chinese herbs in the repair of radiation injury. The p53-TLRs interaction could be exploited to understand and possibly address diseases other than cancer, such as inflammatory and immune diseases. But the relationship between p53 and TLRs in radiation injury is still unclear. Consequently, this project plan to combine traditional Chinese medicine with radiology so as to explore p53-TLRs interaction when radiation injury happens. Meanwhile, type or types of TLRs family that interacts with p53, regulators involved in p53-TLRs interaction, and the effects of radiation protective Chinese herbs in p53-TLRs interaction are also to be researched. This project will supply technical supplies and theoretical basement for the research of radiation injury mechanism, development of radiation protector, and the use of Chinese medicine in radiation injury protection. This project will supply the navy a safe and effective radiation protector, and will provide a foundation for the study of safe and effective radiation protection applied for ordinary people as well.

急性辐射损伤（ARI）是影响海军战士作业及战斗能力，危害其健康甚至威胁生命安全的重要因素，现有辐射防护剂大多作用单一、效价低或毒性较大。中药则有整体调节、疗效确切、毒副作用小等优势。故研制一种经济、高效、无毒的辐射防护中药，是保障我军战士身体健康、免于辐射之苦、提高战斗力的迫切之需。为此，首先要明确辐射损伤机制及中药在损伤修复中的作用机理等关键科学问题。p53-TLRs在炎症性疾病及肿瘤的发生发展中有直接调控关系，但在辐射损伤时的关系不明。本项目拟结合中医药学与放射医学，研究辐射损伤发生时，p53与TLRs的调控关系、与p53发生作用的TLRs种类、参与p53-TLRs调控因子、及防护中药在p53-TLRs中的作用。本项目将为辐射损伤机制研究、防护药研发、中医药在辐射防护中的应用提供技术支持与理论依据；为海军提供安全可靠的抗ARI健康促进措施；也为用于民众的安全有效辐射防护药研究提供基础。

本课题采用BALB/c小鼠建立辐射损伤模型，研究不同照射剂量和照后不同时间点，电离辐射对免疫系统的损伤效应，筛选出益气养血、滋阴解毒为治法的中药复方具有最佳防护效应，并确定了最佳给药剂量和给药时间。通过检测小鼠体重，脏器指数，全血细胞，外周血CD4+/CD8+比例，骨髓、脾脏组织病理切片以及相关免疫、炎症因子表达，研究中药复方对免疫系统辐射损伤的整体防护作用；聚焦天然免疫受体TLRs及其通路，分析TLR4／TLR5和下游相关因子的表达，探究辐射损伤时TLR4（TLR5）/MyD88通路的免疫调节作用和中药复方对通路的影响；课题在研究过程中还观察到，急性辐射损伤会对雄性小鼠睾丸和肠道造成损伤，进而分析了相关损伤机制和中药复方防护效应。.研究表明：（1）Balb/c小鼠在受到60Coγ射线照射后，脾脏、胸腺、全血细胞受损，淋巴细胞亚群比例失调，骨髓细胞凋亡；应用中药复方可在一定程度上保护免疫器官和血细胞，维持淋巴细胞亚群平衡，改善骨髓细胞细胞周期阻滞，降低骨髓细胞凋亡率的趋势，提示中药复方对免疫系统有一定的防护作用。（2）电离辐射可以上调脾脏中TLR4、MyD88、NF-κB、TNF-α等因子的表达，应用中药复方，可通过调节TLR4/MyD88信号通路，修复Treg细胞介导的免疫调节功能，发挥保护作用。（3）中药复方可通过提高辐射损伤雄性小鼠精子的活动率和浓度等，发挥对生殖系统的防护作用；中药复方可修复辐射损伤的小肠上皮组织和肠道机械屏障，并提示可能通过调节凋亡因子、炎症因子等的表达，发挥防护作用。另外，研究中发现不同组织中TLR4在辐射损伤后的表达并不一致，可能与不同组织的识别能力和抗辐射能力相关，而不一致的表达是否会对下游因子及免疫效应产生影响，将在下一步的研究中深化。同时，中医药是通过多靶点、多途径发挥整体防护效应，更多的作用机制也将在后续研究中继续探索。.此研究结果有助于进一步了解电离辐射损伤机制，也为中医药防护急性辐射损伤的研究提供可供参考的研究思路和方法。