Novel erythropoiesis stimulating protein (darbepoetin alfa) alleviates anemia associated with chronic inflammatory disease in a rodent model
Novel erythropoiesis stimulating protein (darbepoetin alfa) alleviates anemia associated with chronic inflammatory disease in a rodent model
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DOI：
10.1016/s0301-472x(01)00723-8
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发表时间：
2001-10-01
影响因子：
2.6
通讯作者：
Molineux, G
中科院分区：
文献类型：
--
作者：
Coccia, MA;Cooke, K;Molineux, G
目标。我们建立了一种非感染性全身炎症的啮齿动物模型，以研究慢性疾病相关性贫血(ACD)的发病机制，评价该模型与人类酸的相似性，并评价新型促红细胞生成素(Darbepoetin Alfa)作为ACD治疗的潜在疗效。用多糖肽多糖聚合物(PG-APS)免疫Lewis大鼠，观察其慢性炎症反应及相关的ACD，并分析达贝泊芬对大鼠全血计数(CBC)、红细胞指数(RBC)及铁代谢的影响。急性发炎的大鼠外周血(PB)、红细胞计数和血红蛋白(Hb)浓度降低，网织红细胞计数增加。慢性炎症时外周血红细胞数量恢复正常，但红细胞仍呈低染色质和小红细胞。结果，这些老鼠仍然处于慢性贫血状态。贫血大鼠的血清促红细胞生成素(EPO)浓度波动，但平均EPO浓度与基线对照水平没有显著差异。贫血大鼠脾切片组织学显示网状内皮铁质沉着症。血清总铁浓度长期处于低水平。体外分离的贫血大鼠腹膜渗出细胞(PEC)经PG-APS刺激后，产生的IL-1α和干扰素-γ(IL-1α)和干扰素(干扰素)-γ明显高于对照组，而肿瘤坏死因子(TNF)-α和IL-10则显著高于对照组。达贝泊丁阿尔法在2至7周内将Hb浓度恢复到基线水平，具体取决于剂量。改进的治疗策略使Hb恢复到基线水平，并在减少剂量的情况下保持这些水平。在这个啮齿动物模型中，ACD与人类的酸密切相关。达贝泊丁阿尔法治疗通过增加RBC的产生和RBC的血红素化，同时减少铁沉着症和低铁血症，逆转了该模型中的ACD。(C)2001年国际实验血液学学会。爱思唯尔科学公司出版。
Objective. We developed a rodent model of noninfectious systemic inflammation to examine the pathogenesis of the associated anemia of chronic disorders (ACD), to evaluate the similarity of this ACD model to human ACID, and to evaluate the potential efficacy of novel erythropoiesis stimulating protein (darbepoetin alfa) as an ACD therapy.Methods. Lewis rats were immunized with peptidoglycan-polysaccharide polymers (PG-APS), the chronic inflammation and associated ACD were characterized, and the effects of darbepoefin alfa treatment on complete blood counts (CBC), red blood cell (RBC) indices, and iron metabolism were analyzed weekly.Results. Acutely inflamed rats had reduced peripheral blood (PB) RBC counts and hemoglobin (Hb) concentrations and increased reticulocyte counts. PB RBC numbers normalized during chronic inflammation, but RBC remained hypochromic and microcytic. Consequently, the rats remained chronically anemic. Anemic rats had fluctuating serum erythropoietin (EPO) concentrations, but mean EPO concentrations never varied significantly from baseline control levels. Histology of anemic rat spleen sections revealed reticuloendothelial siderosis. Total serum iron concentrations were chronically low. Peritoneal exudate cells (PEC) isolated from anemic rats and stimulated with PG-APS in vitro produced more interleukin (IL)-1 alpha and interferon (IFN)-gamma, and significantly more tumor necrosis factor (TNF)-alpha and IL-10 than control cultures. Darbepoetin alfa restored Hb concentrations to baseline levels within 2 to 7 weeks, depending on dosage. A refined treatment strategy restored Hb to baseline and maintained those levels with reduced dosing.Conclusion. ACD in this rodent model closely replicates human ACID. Darbepoetin alfa treatment reversed ACD in this model by increasing RBC production and RBC hemoglobinization while reducing siderosis and hypoferremia. (C) 2001 International Society for Experimental Hematology. Published by Elsevier Science Inc.