基于造血微环境调节和造血细胞保护的血小板生成素抗辐射损伤作用机制研究

Hematopoietic growth factors(HGFs),which promote hematopoiesis, have been applied to treat cytopenia induced by radiation exposure. However, as a symptomatic treatment, HGFs are not efficiency enough for severe hematopoietic syndrome therapy because of that radiation insults hematopoietic system not only hematopoietic cells but also hematopoietic microenviroment. Thus, an efficient therapeutic strategy for hematopoietic syndrome treatment should improve hematopoietic microenviroment while protecting hematopoietic cells from radiation injury. We proved that after radiation exposure, an early high dosage HGFs treatment significantly elevate ARS mice or rehsus monkeys survival rate, prolong their life span and stimulate hematopoiesis recovery. Especially, recombinant human thrombopoietin (rhTPO) displays the best radioprotection efficiency. According to this, to confirm the radioprotection effect and prove the further insight into the radioprotetcion mechanism of rhTPO, we will explore the effect of rhTPO on hematopoietic microenvironment regulation and hematopoietic cells protection in hematopoietic syndrome induced by radiation exposure. Investigating these aspects of HGFs radioprotection mechanisms is essential to enable future manipulation and therapeutic targeting.

造血生长因子（HGFs）因其能刺激造血干祖细胞增殖分化而被用于治疗骨髓型急性放射病（ARS）。然而，其疗效有限。这是由于射线引起造血细胞（种子）受损的同时亦破坏造血微环境（土壤），二者相互影响，彼此加重，单纯刺激"种子"而对"土壤"无作为难以实现造血功能全面重建。因此，对于ARS的治疗应同时着眼于改善造血微环境、保护造血细胞，采取"双管齐下"的策略。基于此，我们提出了大剂量HGFs早期干预救治重症ARS的新策略，并以致死剂量照射小鼠和重症ARS猴为模型进行了验证。结果表明，大剂量HGFs早期干预对重度骨髓型ARS的实验治疗作用明显，以重组人血小板生成素（rhTPO）疗效最为显著。本项目拟在此工作基础上，分别从改善造血微环境和保护造血细胞的角度研究阐述rhTPO的抗辐射损伤作用机制，以期为rhTPO早期干预救治ARS的临床应用提供理论依据，并为寻找ARS治疗新靶标和新措施提供线索。

本课题以致死剂量和非致死剂量照射的C57小鼠和7.0Gy 60Co γ射线照射恒河猴为模型证明了大剂量rhTPO照射前或照射后早期干预具有明显的辐射防护作用，能够提高动物存活率，促进受照动物造血功能全面恢复。对不同剂量照射小鼠模型研究获得了rhTPO的剂量降低系数为1.22。照射前或照射后早期给予大剂量rhTPO是救治骨髓型急性放射病的有效新策略。6.5Gy全身照射引起小鼠全血细胞减少，同时对其造血微环境造成损伤，骨髓基质细胞数量减少，形成CFU-F能力下降。rhTPO能保护6.5Gy γ射线全身照射小鼠造血干/祖细胞，促进其向各系造血细胞分化，进而促进造血细胞全面恢复；发现rhTPO能改善6.5Gy γ射线照射所致的骨髓基质细胞数量减少，并能促进其增殖。rhTPO对造血实质细胞和骨髓基质细胞的双重保护作用是其发挥抗辐射损伤作用的主要途径。