Cyclooxygenase-2 is essential for normal recovery from 5-fluorouracil–induced myelotoxicity in mice,

Cyclooxygenase (COX) plays a key regulatory role in prostaglandin synthesis. COX-2 is inducible and is the major isoform of inflammatory cells. COX-2–deficient mice were shown to have normal basal hematopoiesis and hematology. We hypothesized that COX-2 induction plays a role in the recovery phase of 5-fluorouracil (5-FU) induced bone marrow injury, because significant macrophage-driven phagocytic removal of necrotic debris and stromal cell reorganization of repopulating marrow occur after 5-FU induction of bone marrow necrosis. Hematologic recovery was markedly delayed with moderately severe leukopenia, thrombocytopenia and reticulocytopenia compared to heterozygotes on day 8 or 12 in Cox-2−/− mice. Mild anemia was present in 5-FU–treated Cox-2−/− and Cox-2+/− mice on days 8 and 12, which was more severe in Cox-2−/− mice. Cox-2−/− mice had markedly decreased bone marrow cell counts per femur and reduced numbers of erythroid and myeloid colony-forming cells compared to heterozygote mice on days 8 and 12 post 5-FU. Histologic examination of 5-FU–treated Cox-2−/− mice revealed a failure to repopulate the intact marrow stroma with hematopoietic cells. Accelerated erythropoiesis following phenylhydrazine-induced hemolytic anemia, however, was comparable between Cox-2−/− and Cox+/− mice, as were induced levels of renal erythropoietin mRNA. COX-2 induction is likely a central event in the accelerated hematopoiesis following myelotoxic injury, because recovery from 5-FU–induced myeloablation is markedly impaired in Cox-2−/− mice but is normal after phenylhydrazine induction of anemia.