Deoxygenation Reduces Sickle Cell Blood Flow at Arterial Oxygen Tension
Deoxygenation Reduces Sickle Cell Blood Flow at Arterial Oxygen Tension
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DOI：
10.1016/j.bpj.2016.04.050
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发表时间：
2016-06-21
影响因子：
3.4
通讯作者：
Higgins, John M.
中科院分区：
文献类型：
--
作者：
Lu, Xinran;Wood, David K.;Higgins, John M.
镰状细胞病的大部分发病率和死亡率是由血管阻塞引起的：循环阻塞导致组织缺血和梗死。血管闭塞的后果在临床上见于整个血管树，从相对高氧和高速度的脑动脉到相对低氧和低速度的毛细血管后微静脉。目前流行的血管闭塞模型提出的机制仅与低氧和低速区域相关，这使得我们对镰状细胞病最重要的病理过程的理解存在很大差距。理解血管闭塞的进展进一步受到被认为涉及的多个过程的复杂性的挑战，包括但不限于1）导致流变学受损的脱氧依赖性血红蛋白聚合，2）内皮和白细胞活化，以及3）改变的细胞粘附。在这里，我们选择专注于脱氧依赖的流变过程，努力量化他们的贡献独立于其他过程，可能涉及在体内。我们利用一个实验系统，据我们所知，唯一能够研究压力驱动的血流在生理大小的管在生理血细胞比容在受控的氧合条件下，同时排除内皮细胞，白细胞活化，粘附，炎症和凝血的影响。我们发现，脱氧依赖性流变过程是足够的表观粘度显着增加，动脉血氧分压下，即使没有额外的贡献，炎症，粘附，内皮细胞和白细胞活化的血流速度减慢。我们量化了表观粘度的变化，并为每位患者定义了一组个性化的镰状细胞血流功能方案，这可能对进一步解剖体内血管闭塞机制以及评估患者并发症风险、输血反应和开发中实验疗法的优化至关重要。
The majority of morbidity and mortality in sickle cell disease is caused by vaso-occlusion: circulatory obstruction leading to tissue ischemia and infarction. The consequences of vaso-occlusion are seen clinically throughout the vascular tree, from the relatively high-oxygen and high-velocity cerebral arteries to the relatively low-oxygen and low-velocity postcapillary venules. Prevailing models of vaso-occlusion propose mechanisms that are relevant only to regions of low oxygen and low velocity, leaving a wide gap in our understanding of the most important pathologic process in sickle cell disease. Progress toward understanding vaso-occlusion is further challenged by the complexity of the multiple processes thought to be involved, including, but not limited to 1) deoxygenation-dependent hemoglobin polymerization leading to impaired rheology, 2) endothelial and leukocyte activation, and 3) altered cellular adhesion. Here, we chose to focus exclusively on deoxygenation-dependent rheologic processes in an effort to quantify their contribution independent of the other processes that are likely involved in vivo. We take advantage of an experimental system that, to our knowledge, uniquely enables the study of pressure-driven blood flow in physiologic-sized tubes at physiologic hematocrit under controlled oxygenation conditions, while excluding the effects of endothelium, leukocyte activation, adhesion, inflammation, and coagulation. We find that deoxygenation-dependent rheologic processes are sufficient to increase apparent viscosity significantly, slowing blood flow velocity at arterial oxygen tension even without additional contributions from inflammation, adhesion, and endothelial and leukocyte activation. We quantify the changes in apparent viscosity and define a set of functional regimes of sickle cell blood flow personalized for each patient that may be important in further dissecting mechanisms of in vivo vaso-occlusion as well as in assessing risk of patient complications, response to transfusion, and the optimization of experimental therapies in development.