Cyclooxygenase-2 is essential for normal recovery from 5-fluorouracil-induced myelotoxicity in mice
Cyclooxygenase-2 is essential for normal recovery from 5-fluorouracil-induced myelotoxicity in mice
复制标题
DOI：
10.1016/s0301-472x(99)00087-9
复制
发表时间：
1999-10-01
影响因子：
2.6
通讯作者：
Car, BD
中科院分区：
文献类型：
--
作者：
Lorenz, M;Slaughter, HS;Car, BD
环氧合酶（考克斯）在前列腺素合成中起着关键的调节作用。考克斯-2是可诱导的，并且是炎性细胞的主要同种型。考克斯-2缺陷小鼠显示具有正常的基础造血和血液学。我们假设考克斯-2诱导在5-氟尿嘧啶（5-FU）诱导的骨髓损伤的恢复期起作用，因为在5-FU诱导骨髓坏死后，发生了显著的巨噬细胞驱动的吞噬细胞清除坏死碎片和骨髓基质细胞重组。与杂合子相比，考克斯-2（-/-）小鼠在第8天或第12天的血液学恢复明显延迟，伴有中度重度白细胞减少、血小板减少和网织红细胞减少。在第8天和第12天，5-FU处理的考克斯-2（-/-）和考克斯-2（+/-）小鼠中存在轻度贫血，这在考克斯-2（-/-）小鼠中更严重，在5-FU后第8天和第12天，与杂合子小鼠相比，考克斯-2（-/-）小鼠每个股骨的骨髓细胞计数显著减少，红系和髓系集落形成细胞数量减少，5-FU处理的考克斯-2（-/-）小鼠的组织学检查显示，造血细胞不能重新填充完整的骨髓基质。然而，在苯肼诱导的溶血性贫血后，考克斯-2（-/-）和考克斯（+/-）小鼠之间的加速红细胞生成是相当的，肾促红细胞生成素mRNA的诱导水平也是如此。考克斯-2诱导可能是骨髓毒性损伤后加速造血的中心事件，因为在考克斯-2（-/-）小鼠中，5-FU诱导的骨髓消融的恢复明显受损，但在苯肼诱导贫血后恢复正常，（C）1999 International Society for Experimental Hematology。出版社：Elsevier Science Inc.
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 mas 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 deer-eased 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, (C) 1999 International Society for Experimental Hematology. Published by Elsevier Science Inc.