Synergistic effect of heme and IL‐1 on hematopoietic stromal regeneration after radiation

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Abstract
Results from this study show that a combination of heme and interleukin‐1 (IL‐1) treatment resulted in the most improved recovery of hematopoietic‐stromal regeneration after sublethal irradiation. Less pronounced effects were obtained when heme or IL‐1 were given singly. Sublethal irradiation of mice produced an initial (as early as day 1) intense depression of the hematopoietic system as evidenced by leukopenia. In vivo treatment of animals with heme in combination with IL‐1, accelerated hematopoietic and stromal regeneration as determined by hematopoietic spleen colony forming unit assay (CFU‐S), erythroid (BFU‐E), myeloid (CFU‐GM) clonal cultures, long‐term bone marrow cultures (LTBMC), and the ability to regenerate hematopoiesis by ectopic (renal) stromal hemopoietic transplantation. Sixteen days after irradiation, leukocyte levels in heme and IL‐1 treatment groups were higher than non‐treated animals and were near normal values by 27 days. One day after irradiation, the capacity of stromal progenitors to form new bone and hematopoietic cells (ectopic foci) was severaly impaired, but recovered after 2–4 weeks. This recovery process was accelerated in heme and IL‐1‐treated animals. BFU‐E, CFU‐GM, and CFU‐S capacity was also severely impaired in all animals 1–27 days after irradiation. CFU‐S was only 0.15% of control by day 1 and 5% of control by day 16. Treatment with heme or IL‐1 improved recovery by as much as 70% after 27 days of irradiation. A similar but enhanced recovery was seen for BFU‐E and CFU‐GM, with erythroid recovery the best. Total cellularity, adherent cell layer (ACL) formation, and donogenic capacity by LTBMCs (10 weeks) derived from irradiated animals was severely reduced, whereas the hematopoietic capacity by LTBMCs derived from heme‐ and IL‐1‐treated animals had recovery values similar to non‐irradiated controls. These results suggest therapeutic use of heme and IL‐1 after chemotherapy or bone marrow depression may be beneficial.