Embury S H, Mohandas N, Paszty C, Cooper P, Cheung A T
Division of Hematology and Department of Medicine, San Francisco General Hospital and the University of California-San Francisco, San Francisco, California 94110, USA.
J Clin Invest. 1999 Mar;103(6):915-20. doi: 10.1172/JCI5977.
The accepted importance of circulatory impairment to sickle cell anemia remains to be verified by in vivo experimentation. Intravital microscopy studies of blood flow in patients are limited to circulations that can be viewed noninvasively and are restricted from deliberate perturbations of the circulation. Further knowledge of sickle blood flow abnormalities has awaited an animal model of human sickle cell disease. We compared blood flow in the mucosal-intestinal microvessels of normal mice with that in transgenic knockout sickle cell mice that have erythrocytes containing only human hemoglobin S and that exhibit a degree of hemolytic anemia and pathological complications similar to the human disease. In sickle cell mice, in addition to seeing blood flow abnormalities such as sludging in all microvessels, we detected decreased blood flow velocity in venules of all diameters. Flow responses to hyperoxia in both normal and sickle cell mice were dramatic, but opposite: Hyperoxia promptly slowed or halted flow in normal mice but markedly enhanced flow in sickle cell mice. Intravital microscopic studies of this murine model provide important insights into sickle cell blood flow abnormalities and suggest that this model can be used to evaluate the causes of abnormal flow and new approaches to therapy of sickle cell disease.
循环系统损害对镰状细胞贫血的公认重要性仍有待通过体内实验来验证。对患者血流的活体显微镜研究仅限于可以无创观察的循环系统，并且受到循环系统故意扰动的限制。对镰状细胞血流异常的进一步了解一直等待着人类镰状细胞病的动物模型。我们比较了正常小鼠与转基因敲除镰状细胞小鼠黏膜 - 肠道微血管中的血流情况，这些转基因敲除镰状细胞小鼠的红细胞仅含人类血红蛋白S，且表现出一定程度的溶血性贫血和与人类疾病相似的病理并发症。在镰状细胞小鼠中，除了在所有微血管中观察到血流异常，如血液淤滞外，我们还检测到所有直径小静脉的血流速度降低。正常小鼠和镰状细胞小鼠对高氧的血流反应都很显著，但方向相反：高氧会使正常小鼠的血流迅速减慢或停止，但会显著增强镰状细胞小鼠的血流。对这种小鼠模型的活体显微镜研究为镰状细胞血流异常提供了重要见解，并表明该模型可用于评估血流异常的原因以及镰状细胞病的新治疗方法。
