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 o f 5-fluorouracil (5-FU) induced bone marrow injury, because significant mac rophage-driven phagocytic removal of necrotic debris and stromal cell reorg anization 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 heterozygote s on day 8 or 12 in Cox-2(-/-) mice. Mild anemia mas present in 5-FU-treate d Cox-2(-/-) and Cox-2(+/-) mice on days 8 and 12, which was more severe in Cox-2(-/-) mice, Cox-2(-/-) mice had markedly deer-eased bone marrow cell counts per femur and reduced numbers of erythroid and myeloid colony-formin g cells compared to heterozygote mice on days 8 and 12 post 5-FU, Histologi c examination of 5-FU-treated Cox-2(-/-) mice revealed a failure to repopul ate the intact marrow stroma with hematopoietic cells. Accelerated erythrop oiesis following phenylhydrazine-induced hemolytic anemia, however, was com parable between Cox-2(-/-) and Cox(+/-) mice, as were induced levels of ren al erythropoietin mRNA. COX-2 induction is likely a central event in the ac celerated hematopoiesis following myelotoxic injury, because recovery from 5-FU-induced myeloablation is markedly impaired in Cox-2(-/-) mice but is n ormal after phenylhydrazine induction of anemia, (C) 1999 International Soc iety for Experimental Hematology. Published by Elsevier Science Inc.