Chaotic Mixing of Aerosol in Rhythmically Expanding Lung

描述(申请人提供)：吸入颗粒物在诱发或加重呼吸道疾病方面起主要作用。腺泡区域具有极大的表面积和非常薄而脆弱的血/气屏障，特别容易受到沉积颗粒的破坏作用。要了解肺泡内有毒颗粒物暴露的相关过程，以及通过雾化吸入靶向给药，一个重要的步骤是表征沉积并阐明涉及的机制。以前，我们已经为腺泡沉积研究奠定了新的概念框架，从理论和实验上确立了腺泡气体流动在运动学上是不可逆的，并通过表明以拉伸和折叠模式表现的混沌混合可以是气溶胶沉积的主要贡献因素。这项拟议的项目建立在这些成果的基础上，旨在研究拉伸和折叠运动学的具体机制。我们的主要假设是，潮汐空气锋在吸入时演变成一个巨大的拉伸层，覆盖在腺泡呼吸道的内表面，从而使空气中的气溶胶非常接近肺泡间隔表面，并促进其沉积。在呼气过程中，先前伸展的层的折叠导致气溶胶的侧向输送，这也对沉积过程起到了重要作用。这一新的假设将在三个具体目标上得到严格检验：目标1解决腺泡结构中悬垂和折叠的计算详细机制。目的2解析地研究多分支结构中异步流引起的混沌混合、悬垂和折叠。目的3通过实验研究吸入气雾剂的各种呼吸动作的行为，以及可视化和量化悬垂和折叠的程度。这些实验将在正常大鼠和肺气肿大鼠模型中进行。我们的总体目标是通过这些理论和实验研究的结合，确定在肺外围独特结构中由气流运动学控制的气溶胶沉积的重要机制，从而促进我们对暴露于雾化污染物的风险和靶向治疗药物输送的积极潜力的理解。

DESCRIPTION (provided by applicant): Inhaled particles play a major role in inducing or exacerbating respiratory diseases. The acinar region, with its enormously large surface area and very thin and delicate blood/gas barrier, is particularly vulnerable to the damaging effects of depositing particles. An essential step in understanding toxic particle exposure associated processes in the pulmonary acinus, as well as targeted drug delivery by aerosol inhalation, is to characterize deposition and to elucidate the mechanisms involved. Previously we have laid the foundation of a new conceptual framework for acinar deposition studies by establishing theoretically and experimentally that, contrary to a commonly held view, acinar gas flow can be kinematically irreversible, and by showing that chaotic mixing, manifested by stretching and folding patterns, can be a major contributor to aerosol deposition. This proposed project builds on these achievements and aims to study the specific mechanisms of the stretch and fold kinematics. Our main hypothesis is that tidal air front evolves into an enormously stretched layer upon inhalation which drapes the inner surface of the acinar airways, thus bringing airborne aerosols very close to the alveolar septal surface and promoting their deposition. During exhalation, folding of the previously stretched layer leads to lateral transport of aerosols, also significantly contributing to the deposition process. This novel hypothesis will be rigorously tested in three specific aims: Aim 1 addresses computationally detailed mechanisms of draping and folding in the acinar structure. Aim 2 investigates analytically the chaotic mixing, draping and folding induced by asynchronous flows in multiply branching structures. Aim 3 addresses experimentally the behavior of an inhaled bolus of aerosol with various ventilatory maneuvers, as well as visualizing and quantifying the extent of draping and folding. These experiments will be performed in normal rats and in a rat model of emphysema. Our overall goal is to identify, through the combination of these theoretical and experimental studies, the important mechanisms of aerosol deposition governed by airflow kinematics in the unique structure of the lung periphery and thereby to advance our understanding of the risks of exposure to aerosolized pollutants and the positive potential of targeted therapeutic drug delivery.