Particle kinetics in the postnatally developing lung

描述（由申请人提供）：关于儿童肺部颗粒沉积的知识对于实际估计儿童接触气溶胶所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，但这一问题很少受到关注。目前，我们假设儿童肺是成人肺的小尺寸版本，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巨大的变化。我们之前的研究提供了证据，证明肺外周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粒子运输机制-混沌混合-在成人肺的全肺泡导管中运作。我们假设肺解剖结构的年龄相关变化，如进行性肺泡化，导致颗粒混合和沉积的重大变化，预测沉积高峰发生在非常年幼的儿童，他们的肺已经形成了很大的肺泡，但体积仍然很小。为了验证这一假设，我们建议在我们的专业知识基础上进行一项结合理论和实验方法的研究。(1)我们将通过分析和数值分析来阐明渐进性肺泡化与混沌流动现象的出现以及相关的混合之间的关系。(2)我们将在具有可膨胀壁和不同程度肺泡的简化和控制良好的物理模型中验证这些数学预测的结果。(3)采用不同肺泡形成阶段的发育仔猪切除肺进行吸入暴露和血流可视化实验。这些方法的结果结合在一起，将使我们全面了解肺泡几何形状与肺部混乱混合机制之间的关系，这种机制可能导致颗粒沉积程度的突然变化。同时，该项目的研究结果可能为现实和合理的儿童吸入剂量测定奠定基础，这是一个具有重要临床意义的问题。

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.