Quantitative analysis of mechanisms that govern red blood cell age structure and dynamics during anaemia.
Quantitative analysis of mechanisms that govern red blood cell age structure and dynamics during anaemia.
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DOI：
10.1371/journal.pcbi.1000416
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发表时间：
2009-06
影响因子：
4.3
通讯作者：
Reece SE
中科院分区：
文献类型：
--
作者：
Savill NJ;Chadwick W;Reece SE
数学模型已被证明是阐明和量化控制红细胞年龄结构和种群动态的机制的重要工具。在这里，我们综合了以前的实验数据和数学建模文献中的想法和新的数据，以便测试假设并产生关于这些机制的新预测。其结果是一组关于三个内在机制的相互竞争的假说：循环中RBC浓度对骨髓中未成熟红细胞(网织红细胞)生成率的反馈，网织红细胞从骨髓释放到循环中，以及随后的老化和清除。此外，我们还研究了两种特定于我们的实验系统的机制：苯肼(Phz)和采血对红细胞动力学的影响。我们进行了一系列实验，以量化网织红细胞比例、红细胞浓度和促红细胞生成素浓度在phz诱导的贫血小鼠中的动态变化。通过量化实验误差，我们能够根据我们的数据来拟合和评估每个假设，并使用基于马尔科夫链蒙特卡罗的贝叶斯推理来恢复参数估计。我们发现，在正常情况下，大约3%的网织红细胞早期从骨髓中释放出来，成熟后所有细胞都会立即释放。在循环中，红细胞会随机清除，但最长寿命约为50天。在贫血条件下，网织红细胞生成率与正常和贫血红细胞浓度之差呈线性相关，其释放率与之呈指数相关。PHZ似乎会老化而不是杀死红细胞，而且年轻的红细胞比年长的红细胞受影响更大。采血导致网织红细胞比例出现短暂的非周期性峰值，网织红细胞的发育途径似乎与正常网织红细胞不同。我们还提供了贫血期间血清促红细胞生成素水平昼夜大幅波动的证据。红血球是在骨髓中制造的，并被释放到血流中。它们的种群通过复杂的负反馈机制保持在平衡状态。遗传性疾病、疟疾等病原体和极端的环境变化可以直接通过过早杀死红细胞来改变这种平衡，或者通过破坏这些反馈机制来间接改变这种平衡。在这篇文章中，我们通过将数学模型与实验数据相匹配来测试关于其中一些机制的性质的相互竞争的假设。我们的结果让我们更好地了解了控制红细胞数量的机制，并将改进影响红细胞的疾病模型。
Mathematical modelling has proven an important tool in elucidating and quantifying mechanisms that govern the age structure and population dynamics of red blood cells (RBCs). Here we synthesise ideas from previous experimental data and the mathematical modelling literature with new data in order to test hypotheses and generate new predictions about these mechanisms. The result is a set of competing hypotheses about three intrinsic mechanisms: the feedback from circulating RBC concentration to production rate of immature RBCs (reticulocytes) in bone marrow, the release of reticulocytes from bone marrow into the circulation, and their subsequent ageing and clearance. In addition we examine two mechanisms specific to our experimental system: the effect of phenylhydrazine (PHZ) and blood sampling on RBC dynamics. We performed a set of experiments to quantify the dynamics of reticulocyte proportion, RBC concentration, and erythropoietin concentration in PHZ-induced anaemic mice. By quantifying experimental error we are able to fit and assess each hypothesis against our data and recover parameter estimates using Markov chain Monte Carlo based Bayesian inference. We find that, under normal conditions, about 3% of reticulocytes are released early from bone marrow and upon maturation all cells are released immediately. In the circulation, RBCs undergo random clearance but have a maximum lifespan of about 50 days. Under anaemic conditions reticulocyte production rate is linearly correlated with the difference between normal and anaemic RBC concentrations, and their release rate is exponentially correlated with the same. PHZ appears to age rather than kill RBCs, and younger RBCs are affected more than older RBCs. Blood sampling caused short aperiodic spikes in the proportion of reticulocytes which appear to have a different developmental pathway than normal reticulocytes. We also provide evidence of large diurnal oscillations in serum erythropoietin levels during anaemia. Red blood cells are made in the bone marrow and released into the blood stream. Their population is kept at equilibrium by complex negative feedback mechanisms. Genetic diseases, pathogens such as malaria, and extreme environmental changes can alter this equilibrium, either directly by prematurely killing red blood cells or indirectly through disrupting these feedback mechanisms. In this paper we test competing hypotheses about the nature of some of these mechanisms by fitting mathematical models to experimental data. Our results give us a better understanding of the mechanisms that govern the red blood cell population and will improve models of diseases that affect red blood cells.
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影响因子：
2
作者：
Colijn, C;Mackey, MC
通讯作者：
Mackey, MC
影响因子：
15.9
作者：
HILLMAN, RS
通讯作者：
HILLMAN, RS
DOI：
10.1098/rspb.1992.0156
发表时间：
1992-12-22
影响因子：
4.7
作者：
HELLRIEGEL, B
通讯作者：
HELLRIEGEL, B
影响因子：
56.9
作者：
CLARK, RH;KORST, DR
通讯作者：
KORST, DR
影响因子：
2
作者：
Colijn, C;Mackey, MC
通讯作者：
Mackey, MC