Guo Wen, Schmidt Paul J, Fleming Mark D, Bhasin Shalender
Research Program in Men's Health: Aging and Metabolism, Boston Claude D. Pepper Older Americans Independence Center (W.G., S.B.), and Department of Pathology (P.J.S., M.D.F.), Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
Endocrinology. 2016 Jul;157(7):2937-46. doi: 10.1210/en.2016-1150. Epub 2016 Apr 13.
The anemia of inflammation is a common problem in inflammatory and autoimmune diseases. We characterized a mouse model of anemia of chronic inflammation induced by repeated injections of low doses of heat-killed Brucella abortus (HKBA), and determined the effects of T administration on erythropoiesis in this model. Female C57BL/6NCrl mice were injected weekly with HKBA for 10 wk. Weekly injections of T or vehicle oil were started 4 wk later. Control mice were injected with saline and vehicle oil in parallel. HKBA-injected mice had significantly lower hemoglobin, hematocrit, mean corpuscular volume, reticulocyte hemoglobin, transferrin saturation (TSAT), and tissue nonheme iron in liver and spleen, enlarged spleen, and up-regulated hepatic expression of inflammatory markers, serum amyloid A1, and TNFα, but down-regulated IL-6, bone morphogenic protein 6, and hepcidin compared with saline controls. HKBA also reduced serum hepcidin and increased serum erythropoietin. Bone marrow erythroid precursors were substantially reduced in HKBA-injected mice. Cotreatment with T increased the percentage of late-stage erythroid precursors in the bone marrow relative to HKBA-injected and saline controls and reversed HKBA-induced suppression of hemoglobin and hematocrit. T also normalized serum erythropoietin, TSAT, and reticulocyte hemoglobin without correcting the expression of the hepatic inflammation markers. Conclusions are that low-dose HKBA induces moderate anemia characterized by chronic inflammation, decreased iron stores, and suppression of erythroid precursors in the bone marrow. T administration reverses HKBA-induced anemia by stimulating erythropoiesis, which is associated with a shift toward accelerated maturation of erythroid precursors in the bone marrow.
炎症性贫血是炎症和自身免疫性疾病中常见的问题。我们对通过反复注射低剂量热灭活布鲁氏菌（HKBA）诱导的慢性炎症性贫血小鼠模型进行了表征，并确定了T给药对该模型中红细胞生成的影响。雌性C57BL/6NCrl小鼠每周注射HKBA，持续10周。4周后开始每周注射T或赋形剂油。对照小鼠并行注射生理盐水和赋形剂油。与生理盐水对照组相比，注射HKBA的小鼠血红蛋白、血细胞比容、平均红细胞体积、网织红细胞血红蛋白、转铁蛋白饱和度（TSAT）以及肝脏和脾脏中的组织非血红素铁显著降低，脾脏肿大，肝脏中炎症标志物、血清淀粉样蛋白A1和TNFα的表达上调，但IL-6、骨形态发生蛋白6和铁调素下调。HKBA还降低了血清铁调素并增加了血清促红细胞生成素。注射HKBA的小鼠骨髓红系前体细胞大幅减少。与注射HKBA和生理盐水的对照组相比，T联合治疗增加了骨髓中晚期红系前体细胞的百分比，并逆转了HKBA诱导的血红蛋白和血细胞比容抑制。T还使血清促红细胞生成素、TSAT和网织红细胞血红蛋白恢复正常，但未纠正肝脏炎症标志物的表达。结论是低剂量HKBA诱导中度贫血，其特征为慢性炎症、铁储备减少和骨髓红系前体细胞受抑制。T给药通过刺激红细胞生成逆转HKBA诱导的贫血，这与骨髓中红系前体细胞加速成熟的转变有关。
