Biomechanics of red blood cells in human spleen and consequences for physiology and disease
Biomechanics of red blood cells in human spleen and consequences for physiology and disease
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DOI：
10.1073/pnas.1606751113
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发表时间：
2016-07-12
影响因子：
11.1
通讯作者：
Suresh, Subra
中科院分区：
文献类型：
--
作者：
Pivkin, Igor V.;Peng, Zhangli;Suresh, Subra
当检测到红细胞（RBC）的大小、形状和变形能力发生变化时，可以从循环中清除RBC。该功能由脾特异性结构的内皮间缝隙（IES）调节。在这里，我们提出了一个独特的生理框架，通过量化的生物物理限制红细胞通过IES的红细胞疾病的预后标志物的发展，使用基于耗散粒子动力学的计算模拟。结果表明，脾脏根据RBC的几何形状选择RBC进行持续循环，这与先前的体内观察结果一致。伴随分析提供了与健康RBC的表面积和体积相关的临界界限，超过该界限，RBC不能通过IES的“体能测试”，支持独立实验。我们的研究结果表明，脾脏在决定健康红细胞的大小和形状的分布中起着重要的作用。由于受感染红细胞的机械滞留影响疟疾发病机制，我们研究了感染恶性疟原虫的红细胞在穿过IES时的关键生物物理参数。与实验结果一致，发现受感染的红细胞的表面积损失比其膜硬度是脾滞留的更重要的决定因素。模拟提供了对IES上的压力梯度对RBC保留的影响的见解。通过提供定量的生物物理限制红细胞通过IES，在脾脏中的最西部的循环瓶颈，我们的研究结果提供了一个广泛的方法来开发定量标记的疾病，如遗传性球形红细胞增多症，地中海贫血症，疟疾。
Red blood cells (RBCs) can be cleared from circulation when alterations in their size, shape, and deformability are detected. This function is modulated by the spleen-specific structure of the interendothelial slit (IES). Here, we present a unique physiological framework for development of prognostic markers in RBC diseases by quantifying biophysical limits for RBCs to pass through the IES, using computational simulations based on dissipative particle dynamics. The results show that the spleen selects RBCs for continued circulation based on their geometry, consistent with prior in vivo observations. A companion analysis provides critical bounds relating surface area and volume for healthy RBCs beyond which the RBCs fail the "physical fitness test" to pass through the IES, supporting independent experiments. Our results suggest that the spleen plays an important role in determining distributions of size and shape of healthy RBCs. Because mechanical retention of infected RBC impacts malaria pathogenesis, we studied key biophysical parameters for RBCs infected with Plasmodium falciparum as they cross the IES. In agreement with experimental results, surface area loss of an infected RBC is found to be a more important determinant of splenic retention than its membrane stiffness. The simulations provide insights into the effects of pressure gradient across the IES on RBC retention. By providing quantitative biophysical limits for RBCs to pass through the IES, the narrowest circulatory bottleneck in the spleen, our results offer a broad approach for developing quantitative markers for diseases such as hereditary spherocytosis, thalassemia, and malaria.