Limitations of a mouse model of sickle cell anemia
Limitations of a mouse model of sickle cell anemia
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DOI：
10.1006/bcmd.2002.0503
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发表时间：
2002-03-01
影响因子：
2.3
通讯作者：
Blau, CA
中科院分区：
文献类型：
--
作者：
Ieremia, J;Blau, CA
我们的目标是利用已建立的镰状细胞性贫血小鼠模型来开发一种明确的方法来测试新疗法，以生存为终点。比较了三组不同小鼠在各种挑战后的存活率：（a）仅表达人血红蛋白-S（（h）β（s））的镰状细胞小鼠； (b) 表达人血红蛋白 S 和鼠 β 主要珠蛋白 ((h)beta(m)(s)beta) 的同窝仔猪； (c) 野生型 C57BL/6 小鼠 (wt)。测试了两种类型的挑战。第一组研究基于最近的观察结果，表明粒细胞集落刺激因子（G-CSF）可能会导致镰状细胞病患者出现严重并发症。虽然 (h)beta(s) 小鼠在基线时比 (h)beta(m)(s)beta 小鼠具有更高的中性粒细胞计数，但 (h)beta(s) 小鼠耐受多种不同剂量和方案的人或鼠 G-CSF，没有不良反应。第二种类型的挑战测试了镰状细胞小鼠是否表现出对血红蛋白脱氧作用增强的敏感性。通过单次腹膜内注射亚硫酸氢钠或通过缺氧 1 小时来完成急性血红蛋白脱氧。与 (h)beta(m)(s)beta 或 wt 小鼠相比，两种干预均未导致 (h)beta(s) 小鼠的存活率显着不同。每周两次慢性暴露于缺氧（每次暴露 1 小时）也未能在 12 周内使 (h)beta(s) 小鼠、(h)beta(m)(s)beta 和 wt 小鼠之间的存活率产生显着差异。我们的结果表明，G-CSF 给药和缺氧都不会加剧该镰状细胞小鼠模型与正常对照之间的生存差异。 (C) 2002 年爱思唯尔科学（美国）。
We aimed to use an established murine model of sickle cell anemia to develop an unambiguous method for testing new therapies, with survival as an end point. Survival rates following various challenges were compared for three different groups of mice: (a) sickle cell mice expressing human hemoglobin-S exclusively ((h)beta(s)); (b) littermates that expressed both human hemoglobin S and murine beta major globin ((h)beta(m)(s)beta); and (c) wild-type C57BL/6 mice (wt). Two types of challenge were tested. The first set of studies was based upon recent observations indicating that granulocyte-colony stimulating factor (G-CSF) can precipitate severe complications in patients with sickle cell disease. While (h)beta(s) Mice had higher neutrophil counts than,(h)beta(m)(s)beta mice at baseline, (h)beta(s) mice tolerated several different doses and schedules of either human or murine G-CSF without adverse effects. A second type of challenge tested whether sickle cell mice exhibit an enhanced susceptibility to hemoglobin deoxygenation. Acute hemoglobin deoxygenation was accomplished either by a single intraperitoneal injection of sodium bisulfite or by a 1-h exposure to hypoxia. Neither intervention resulted in a significantly different survival rate for (h)beta(s) mice compared to either (h)beta(m)(s)beta or wt mice. Chronic twice-weekly exposures to hypoxia (1 h per exposure) also failed to produce significant differences in survival rates between (h)beta(s) mice, (h)beta(m)(s)beta, and wt mice over a period of 12 weeks. Our results demonstrate that neither G-CSF administration nor hypoxia accentuates survival differences between this model of sickle cell mouse and normal controls. (C) 2002 Elsevier Science (USA).