Particle kinetics in the postnatally developing lung

出生后发育中的肺部的粒子动力学

• 批准号: 7274835
• 负责人: AKIRA TSUDA
• 金额: $ 23.33万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7274835
• 关键词: Acinus organ component; Address; Adult; Aerosols; Age; Air; Air Pollution; Alveolar; Alveolar Duct; Alveolus; Anatomy; Animal Model; Appearance; Architecture; Area; Asthma; Attention; Behavior; Birth; Breathing; Bronchitis; Child; Clinical; Condition; Confocal Microscopy; Deposition; Depth; Development; Dose; Duct (organ) structure; Environmental Pollutants; Foundations; Frequencies; Goals; Growth; Guidelines; Health; Human; Imagery; In Vitro; Inhalation Exposure; Kinetics; Knowledge; Lead; Liquid substance; Lung; Lung diseases; Magnetometries; Measures; Mechanics; Modeling; Motion; Numbers; Particulate; Pattern; Personal Satisfaction; Pharmaceutical Preparations; Risk; Role; Staging; Structure; Surface; System; Testing; Therapeutic; Tidal Volume; Time; Work; age group; age related; base; dosimetry; lung acinus structure; lung development; particle; physical model; postnatal; postnatal human; research study; size

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.

描述（由申请人提供）：有关儿童肺部颗粒沉积的知识对于实际估计儿童气溶胶暴露所造成的健康风险至关重要，并且对于确定吸入治疗药物的正确剂量至关重要，但这个问题很少受到关注。目前，假设儿童肺是成人肺的缩小版，并使用按比例缩小的成人肺模型来评估沉积效率。然而，众所周知，在出生后发育过程中，肺部不仅尺寸不断增大，而且结构也发生了巨大的变化。我们之前的研究提供的证据表明，肺周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传输机制——混沌混合——在成人肺部的完全肺泡导管中运行。我们假设肺解剖结构中与年龄相关的变化（例如渐进性肺泡化）会导致颗粒混合和沉积的重大变化，预测沉积高峰出现在肺部已经大部分肺泡化但尺寸仍然很小的幼儿身上。为了检验这一假设，我们建议基于我们的专业知识，结合理论和实验方法进行一项研究。 （1）我们将进行解析和数值分析，以阐明渐进泡腾与混沌流现象和相关混合的出现之间的关系。 (2) 我们将在具有可膨胀壁和不同程度泡孔的简化且控制良好的物理模型中测试这些数学预测的结果。 (3)将处于不同肺泡发育阶段的发育仔猪的肺切除，用于进行吸入暴露和流动可视化实验。这些方法的结果将使我们全面了解肺泡几何形状与肺部混沌混合机制的出现之间的关系，这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儿童实际且合理的吸入剂量测定奠定基础——这具有重要的临床意义。

项目成果

Discovery of unique and ENM- specific pathophysiologic pathways: Comparison of the translocation of inhaled iridium nanoparticles from nasal epithelium versus alveolar epithelium towards the brain of rats.

• DOI: 10.1016/j.taap.2016.02.004
• 发表时间: 2016-05-15
• 期刊: Toxicology and applied pharmacology
• 影响因子: 3.8
• 作者: Kreyling WG

Air-blood barrier translocation of tracheally instilled gold nanoparticles inversely depends on particle size.

• DOI: 10.1021/nn403256v
• 发表时间: 2014-01-28
• 期刊: ACS NANO
• 影响因子: 17.1
• 作者: Kreyling, Wolfgang G.;Hirn, Stephanie;Moeller, Winfried;Schleh, Carsten;Wenk, Alexander;Celik, Guelnaz;Lipka, Jens;Schaeffler, Martin;Haberl, Nadine;Johnston, Blair D.;Sperling, Ralph;Schmid, Guenter;Simon, Ulrich;Parak, Wolfgang J.;Semmler-Behnke, Manuela
• 通讯作者: Semmler-Behnke, Manuela