Pre-irradiation administration of nilestriol promotes hematopoietic recovery but increases early mortality risk and impairs wound healing after total-body irradiation combined with wound trauma

Estrogens are frequently employed as radioprotective agents in nuclear emergencies, yet their effects on radiation combined injury (RCI) are poorly understood. This study evaluated the impact of nilestiol on radiation-wound combined injury (R-W-CI). Mouse models included 6.0 and 8.0 Gy total body irradiation (TBI), 2.0% of the total body surface area (TBSA) skin wound trauma, and R-W-CI (6.0 or 8.0 Gy TBI followed by a 2% TBSA wound). Nilestriol was administered 3 and 1 day pre-injury. The outcomes assessed included 30-day survival, weight changes, peripheral blood analysis, wound closure, bone marrow-derived clonogenic activity, flow cytometric analysis of hematopoietic stem and progenitor cells, and splenic extramedullary hematopoiesis. Nilestriol significantly improved 30-day survival rate in mice subjected to 8.0 Gy TBI and enhanced hematopoietic recovery in those exposed to 6.0 Gy TBI. In wound-only models, nilestriol suppressed early inflammatory cytokines and impaired wound closure. For R-W-CI model with 8.0 Gy, nilestriol significantly improved the 30-day survival rate but increased the risk of early mortality. For R-W-CI with 6.0 Gy, nilestriol significantly promoted hematopoietic recovery, but led to a significant delay in wound healing by more pronounced inhibitory effects on the early inflammatory response in wounds of R-W-CI. No gender differences were observed in the effects of nilestriol. Additionally, Splenic extramedullary hematopoiesis was inhibited in nilestriol pretreatment groups. These findings suggest that pre-irradiation administration of nilestriol can mitigate R-W-CI effects but requires careful consideration due to potential negative impacts on both systemic and local levels.