Particle kinetics in the postnatally developing lung

说明(由申请者提供)：关于儿童肺部颗粒沉积的知识对于现实地估计儿童暴露在气雾剂中造成的健康风险以及确定吸入治疗药物的正确剂量至关重要，但这一问题几乎没有受到关注。目前，人们假设儿童的肺是成人肺的小型版本，并使用缩小的成人肺模型来评估沉积效率。然而，众所周知，在出生后的发育过程中，肺不仅在大小上增长，而且在结构上也发生了戏剧性的变化。我们以前的研究提供了证据，证明肺外围的结构是颗粒行为的主要决定因素；特别是，我们发现了一种新的颗粒运输机制--混沌混合--在成人肺的完全肺泡化的管道中工作。我们假设肺解剖中与年龄相关的变化，如进行性肺泡形成，会导致颗粒混合和沉积的主要变化，并预测沉积的峰值出现在非常年幼的儿童身上，这些肺已经基本上形成了肺泡，但体积仍然很小。为了验证这一假设，我们建议在我们专业知识的基础上，进行一项理论和实验相结合的研究。(1)我们将进行解析和数值分析，以阐明渐进式泡化与混沌流动现象和相关混合现象的出现之间的关系。(2)我们将在简化和控制良好的物理模型中检验这些数学预测的结果，这些物理模型具有可扩展的壁和不同程度的肺泡。(3)取发育中不同肺泡阶段仔猪的肺，进行吸入暴露和流动显示实验。这些方法的结果将使我们全面了解肺泡几何形状与肺中可能导致颗粒沉积程度突变的混沌混合机制的出现之间的关系。同时，该项目的研究结果可能会为儿童吸入剂量学的现实和合理基础奠定基础--这是一项具有重要临床意义的事情。

DESCRIPTION (provided by applicant): Knowledge on particle deposition in children's lungs is essential for realistic estimates of health risks posed by aerosol exposure of children, and also to determine the correct dose for therapeutic drugs delivered by inhalation, but this problem has received little attention. Currently, it is assumed that children's lungs are a small-size version of the adult one, and scaled-down adult lung models are used for the assessment of deposition efficiency. It is well established, however, that during postnatal development the lungs are not only growing in size, but they also undergo dramatic structural changes. Our previous studies provided evidence that the structure of the lung periphery is a major determinant of particle behavior; particularly, we have discovered a new mechanism of particle transport -chaotic mixing-, operating in the fully alveolated ducts of adult lungs. We hypothesize that age-associated changes in lung anatomy, such as progressive alveolation, lead to major changes in particle mixing and deposition, predicting that deposition peaks in very young children with lungs that have become largely alveolated already but are still small in size. To test this hypothesis, we propose to perform a study combining theoretical and experimental approaches building on our expertise. (1) We will perform analytical and numerical analyses to elucidate the relationship between progressive alveolation and the appearance of chaotic flow phenomena and associated mixing. (2) We will test the findings of these mathematical predictions in simplified and well-controlled physical models with expandable walls and different degrees of alveolation. (3) Excised lungs of developing piglets at different stages of alveolation will be used to do inhalation exposure and flow visualization experiments. The results of these approaches taken together will give us a comprehensive view of the relationship between alveolar geometry and the appearance of chaotic mixing mechanisms in the lung that may result in a sudden change in the extent of particle deposition. At the same time the findings of this project may lay down the foundation for realistic and rationally based inhalation dosimetry in children - a matter of great clinical importance.