REQUIREMENTS FOR THERAPEUTIC INHIBITION OF SICKLE HEMOGLOBIN GELATION
REQUIREMENTS FOR THERAPEUTIC INHIBITION OF SICKLE HEMOGLOBIN GELATION
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DOI：
10.1038/275238a0
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发表时间：
1978-01-01
期刊：
影响因子：
64.8
通讯作者：
EATON, WA
中科院分区：
文献类型：
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作者：
SUNSHINE, HR;HOFRICHTER, J;EATON, WA
血红蛋白 S 凝胶化的动力学研究表明，反应开始后，聚合物出现之前有明显的延迟1-5。延迟时间对生理变量极其敏感，例如总血红蛋白浓度和配体饱和分数，并且对 pH、盐浓度和温度（接近 37 °C）1,5–10 中等敏感。这些变量的变化减少了延迟时间，似乎与镰状细胞病临床严重程度的增加有关1,11。这些发现可以通过病理生理学机制来解释，即细胞内凝胶化延迟时间相对于毛细血管通过时间的减少，增加了毛细血管内镰状化的可能性；微循环可能受阻，从而导致组织缺氧和器官损伤。因此，延迟时间的增加，允许细胞在凝胶化开始之前逃离狭窄的毛细血管，预计将导致疾病的改善1,11。我们在这里展示旨在帮助回答以下问题的动力学实验结果：必须增加多少延迟时间才能在患者中获得给定的治疗效果？
KINETIC studies on haemoglobin S gelation have shown that following initiation of the reaction there is a pronounced delay before the appearance of the polymer1–5. The delay time is extremely sensitive to physiological variables, such as total haemoglobin concentration and fractional saturation with ligand, and moderately sensitive topH, salt concentration and temperature (near 37 °C)1,5–10. Changes in these variables which decrease the delay time seem to be associated with increased clinical severity of sickle cell disease1,11. These findings have been explained by a pathophysiological mechanism in which a decrease in the delay time of intracellular gelation, relative to the capillary transit time, increases the probability of intracapillary sickling; blockage of the microcirculation is then possible, with consequent tissue anoxia and organ damage. An increase in the delay time, permitting cells to escape the narrow capillaries before gelation has begun, is therefore predicted to result in amelioration of the disease1,11. We present here results of kinetic experiments designed to help answer the question: how much must the delay time be increased to obtain a given therapeutic effect in patients?