(178) “Red Blood Cells are critical determinants of survival in radiation-induced hematologic injury”

Introduction/Rationale: Whole-body ionizing radiation induces acute hematopoietic injury that critically limits survival. While radiation-induced leukocyte loss has been extensively characterized, the role of red blood cell (RBC) depletion in determining mortality remains poorly understood. Because RBCs are vital cells of blood, studying RBCs following radiation can uncover key determinants of survival and therapeutic targets in hematopoietic injury.

Methods: Wild-type C57BL/6 mice (Male and Female, 8–10 weeks of age) were exposed to 5 Gy total body irradiation (TBI), and peripheral blood parameters were monitored longitudinally on day 0 to day 60 post-radiation. White blood cell (WBC), red blood cell (RBC), and hemoglobin levels were quantified at each time point using complete blood counts (CBCs). RBC morphology was examined by Wright–Giemsa staining to assess structural abnormalities. To evaluate the functional impact of RBC loss, an additional cohort of mice received lethal 6 Gy TBI and were transfused with RBCs on days 2 and 5 post-irradiation, while another group of mice received PBS as a control. Survival was monitored for all groups.

Results: WBC counts declined rapidly, showing >90% reduction by day 1, with recovery beginning after day 20. In contrast, RBC counts and hemoglobin levels exhibited a delayed but progressive decline, reaching their lowest levels around day 15. Radiation also caused distinct RBC morphological abnormalities, including poikilocytes, echinocytes, and schistocytes. The start of mortality in irradiated mice closely coincided with the loss of RBCs and hemoglobin. Remarkably, transfusion of RBCs on days 2 and 5 post-irradiation significantly improved survival, 40% lethality in transfused mice vs. 100% in controls; P = 0.0022.

Conclusion: These findings identify that RBC depletion is a major driver of radiation-induced mortality. Protection or restoration of RBCs strikingly improves survival, highlighting RBC maintenance as a critical therapeutic target in hematopoietic radiation injury.