Thrombopoietin protects mice from mortality and myelosuppression following high-dose irradiation: importance of time scheduling.
Thrombopoietin is the major regulator of platelet production and a stimulator of multilineage hematopoietic recovery following irradiation. The efficacy of three different schedules of thrombopoietin administration was tested on blood cell counts, hematopoietic bone marrow progenitors, and 30-day animal survival in C57BL6/J mice receiving a total body irradiation, with doses ranging from 7 to 10 Gy. A single dose of murine thrombopoietin was injected 2 h before, 2 h after, or 24 h after irradiation. Thrombopoietin promoted multilineage hematopoietic recovery in comparison to placebo up to 9 Gy at the level of both blood cells and bone marrow progenitors, whatever the schedule of administration. The injection of thrombopoietin 2 h before or 2 h after irradiation equally led to the best results concerning hematopoietic recovery. On the other hand, thrombopoietin administration promoted 30-day survival up to 9 Gy with the highest efficacy obtained when thrombopoietin was injected either 2 h before or 2 h after irradiation. However, when its injection was delayed at 24 h, thrombopoietin had almost no effect on survival of 9 Gy irradiated mice. Altogether, our results show that the time schedule for thrombopoietin injection is of critical importance and when thrombopoietin is administered before or shortly after irradiation, it efficiently promotes mice survival to supra-lethal irradiation (up to 9 Gy) in relation with hematopoietic recovery.
Mouthon
Marc-André
MA
Institut de Protection et de Sûreté Nucléaire, IPSN, Fontenay-aux-Roses, France. marc.andre.mouthon@ipsn.fr
Van der Meeren
Anne
A
Vandamme
Marie
M
Squiban
Claire
C
Gaugler
Marie-Hélène
MH
D000818:Animals; D001772:Blood Cell Count; D004305:Dose-Response Relationship, Drug; D006098:Granulocytes / Q000187:drug effects; D006410:Hematopoiesis / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011833:Radiation Injuries, Experimental / Q000097:blood* / Q000188:drug therapy*; D016019:Survival Analysis; D013926:Thrombopoietin / Q000627:therapeutic use*; D013997:Time Factors
D013926:Thrombopoietin