Mouthon M A, Van der Meeren A, Gaugler M H, Visser T P, Squiban C, Gourmelon P, Wagemaker G
Institut de Protection et de Sûreté Nucléaire, IPSN, Fontenay-aux-Roses, France.
Int J Radiat Oncol Biol Phys. 1999 Mar 1;43(4):867-75. doi: 10.1016/s0360-3016(98)00477-5.
The therapeutic potential of thrombopoietin (TPO), the major regulator of platelet production, was evaluated for hematopoietic recovery and survival in mice following lethal and supralethal total body irradiation (TBI).
Hematopoietic recovery was studied in C57BL6/J mice after 8 Gy TBI (gamma-rays). Survival experiments were performed with C57BL6/J and BCBA F1 mice. Two protocols of TPO administration were evaluated: treatment for 7 consecutive days (7 x 0.3 microg/mice) beginning 2 h after exposure, or a single dose (0.3 microg/mice) administered 2 h after irradiation.
TPO improved the platelet nadir and accelerated the platelet reconstitution of irradiated mice in comparison to placebo-treated mice. Recovery of neutrophils and erythrocytes was stimulated as well. TPO induced an accelerated recovery of hematopoietic progenitors and immature multilineage progenitors in bone marrow and spleen. In addition, TPO administration induced approximately 90% survival of 8 Gy irradiated C57BL6/J mice, a TBI dose which resulted in 100% mortality within 30 days for placebo-treated mice. Single TPO administration was as effective as repeated injections for hematopoietic recovery and prevention of mortality. Dose-effect survival experiments were performed in BCBA F1 mice and demonstrated that TPO shifted the LD50/30 from approximately 9.5 Gy to 10.5 Gy TBI given as a single dose, and from 14 Gy to as high as 17 Gy when TBI was given in three equal doses, each separated by 24 h.
These results demonstrate that the multilineage hematopoietic effects of TPO may be advantageously used to protect against lethal bone marrow failure following high dose TBI.
评估血小板生成的主要调节因子血小板生成素（TPO）对致死性和超致死性全身照射（TBI）后小鼠造血恢复和生存的治疗潜力。
在C57BL6/J小鼠接受8 Gy TBI（γ射线）后研究造血恢复情况。用C57BL6/J和BCBA F1小鼠进行生存实验。评估了两种TPO给药方案：照射后2小时开始连续7天治疗（7×0.3微克/小鼠），或照射后2小时给予单剂量（0.3微克/小鼠）。
与安慰剂治疗的小鼠相比，TPO改善了照射小鼠的血小板最低点并加速了血小板重建。中性粒细胞和红细胞的恢复也受到刺激。TPO诱导骨髓和脾脏中造血祖细胞和未成熟多系祖细胞加速恢复。此外，给予TPO可使8 Gy照射的C57BL6/J小鼠的存活率约为90%，而该TBI剂量对安慰剂治疗的小鼠在30天内导致100%死亡。单次给予TPO在造血恢复和预防死亡方面与重复注射一样有效。在BCBA F1小鼠中进行了剂量效应生存实验，结果表明，TPO将单次给予的TBI的LD50/30从约9.5 Gy提高到10.5 Gy，当TBI分三次等剂量给予，每次间隔24小时时，从14 Gy提高到高达17 Gy。
这些结果表明，TPO的多系造血作用可有利地用于预防高剂量TBI后致死性骨髓衰竭。
