Prostaglandin E2 Promotes Recovery of Thymus in Survivors of the Hematopoietic Acute Radiation Syndrome (H-ARS)

We have previously developed a murine model of the hematopoietic acute radiation syndrome [H-ARS, total body irradiated (TBI)] and delayed effects of acute radiation exposure (DEARE) for efficacy testing of potential medical countermeasures (MCM) against these two syndromes. Using this model, we have previously reported that prophylactic use of 16,16 dimethyl-prostaglandin E2 (dmPGE2), a long-acting formulation of PGE, before irradiation significantly increases 30-day survival rate. The current study investigated the effects of the prophylactic use of dmPGE2 with or without therapeutic use of dmPGE2 in survivors on long-term thymus recovery in H-ARS survivors at 6 and 12-months post-LD70/30 (872cGy, 137Cs, 95.2±4.8 cGy/min). Mice were irradiated at 12 weeks of age and then injected subcutaneously with dmPGE2 (1 dose of 35 ug dmPGE2/mouse) or vehicle (Veh; ethanol/PBS solution) at 30'' or -1hr pre-TBI. Survivors were injected monthly with dmPGE2 or Veh and then analyzed for evidence of thymic reconstitution at 6 and 12 months.post-TBI. The three test groups were: prophylactic dmPGE2 + monthly dmPGE2 (PP), prophylactic dmPGE2 + monthly Veh (PV), and prophylactic Veh + monthly Veh (VV), n = 3-6 mice/group. Thymus weight and cellularity of mice in the dmPGE groups, PV and PP, were increased compared to Veh both at 6-months and 12-months post-TBI (p <0.05). The difference was not related to body weight. No difference was observed between PP and PV group. The number of thymocyte subgroups (CD4 single positive, CD8 single positive, double positive and double negative) was also increased in PV and PP mice. Complete blood count (CBC) was also analyzed in the same mice. The VV group showed myeloid skewing, evidenced as an increase in neutrophils and decrease in lymphocytes. The PV and PP groups both exhibited reversal of myeloid skewing, and once again dmPGE maintenance did not provide extra benefit. Thymic progenitors in bone marrow, known as the lymphoid-primed multipotent progenitors (LMPP, Lin-Kit+Sca1+Flt3hiCD34+) and common lymphoid progenitor (CLP, Lin-IL7R+KitloSca1lo Flt3+) were also increased in PV and PP groups compared with VV group (p <0.05). No difference was observed in common myeloid progenitors (CMP), granulocyte-macrophage progenitors (GMP), and MEP (megakaryocyte-erythroid progenitor) between PP and PV group. Competitive bone marrow transplantation showed more than 10 times higher donor-derived chimerism in the thymus of PP and PV mice compared with the VV group. Again, no difference was observed between PP and PV group. In conclusion, these data show that dmPGE2, given before irradiation, protects thymic settling progenitors in bone marrow, resulting in reversal of thymic involution, increased peripheral lymphocytes, and partial alleviation of the myeloid skewing observed in radiation survivors. dmPGE maintenance does not bring extra benefit. F unded by Department of the Army PR140433P1 and NIAID 1U01AI107340-01.