Quantitative MRI-based Assessment of Aerosol Deposition in the Lung

描述(由申请人提供)：详细了解气雾剂在肺部的去向，对于了解暴露在空气中的颗粒物(PM)和感染剂的影响以及评估吸入性药物治疗的效果至关重要。对人体外周气溶胶沉积(DE)进行详细但非侵入性的研究几乎是不可能的。因此，了解肺内气雾剂的命运需要使用动物模型和/或计算模型，在动物模型中可以使用更具侵入性的技术。在过去的十年里，磁共振成像(MRI)已经成为临床医学和生命科学研究中的一种主要成像方式，并已成功地应用于各种肺部研究。最近还表明，使用具有很高空间分辨率(50-100 5m)的核磁共振扫描仪，可以直接测量组织中单个微米大小的氧化铁颗粒的位置。这项研究的两个主要目标是：1)改进我们的MRI技术，以测量大鼠模型中的气溶胶DE模式；2)应用这项技术来表征肺气肿对气溶胶DE模式的影响。我们将首先将雾化荧光标记的氧化铁颗粒运送到健康的麻醉大鼠。使用高分辨率磁共振成像，我们将表征整个大鼠肺的气溶胶DE模式，并确定从肺叶到亚叶大小不同的肺子区域的相对DE。我们还将通过荧光测定法对相同动物的气溶胶DE模式进行表征，以验证MRI数据。利用这项新的MRI技术，我们将研究肺气肿对气溶胶DE的影响。在气雾剂暴露前6周，Wistar大鼠将通过气管内注入胰腺弹性酶来诱发肺气肿。然后，健康和肺气肿的大鼠将在受控呼吸模式下用雾化氧化铁颗粒(1微米和3微米)进行气管通风。动物将通过核磁共振成像来生成气溶胶DE的区域地图。肺气肿的影响将通过对变异系数的分析以及在健康和肺气肿大鼠身上获得的DE图的比较来确定。这项拟议的研究将提供肺内气溶胶DE模式的详细定量描述，涉及三个主要领域：1)暴露在空气中的PM，2)肺气肿疾病，3)通过雾化吸入改善治疗。有越来越多的证据表明，暴露在环境PM中会增加易感人群的心肺发病率和死亡率。对颗粒物DE模式的了解不仅将提供气溶胶DE的定量评估，而且还将为表征PM暴露引起的宿主免疫反应提供有洞察力的信息。更好地了解气雾剂在肺中的命运也将有益于气雾剂药物治疗，因为这将使药物能够更好地靶向其预定的作用部位。最后，肺气肿是45岁以上人群中最常见的慢性病之一，它改变了肺部气体流动，从而改变了吸入颗粒物在肺部的穿透和随后的DE。MRI技术的验证将为阐明肺气肿对气溶胶DE的影响提供重要的工具。这样的验证也将使未来对众多不同肺部疾病模型的MRI研究成为可能。项目简介：我们建议通过核磁共振成像(MRI)定量评估大鼠肺内因气溶胶暴露而沉积的颗粒的分布。拟议的研究与公共卫生有关，因为1)它将为描述暴露在颗粒物中的宿主免疫反应的特征提供有洞察力的信息，2)将有益于气雾剂药物治疗，因为它将允许更好地将药物定向到所需的肺部区域，以及3)将阐明肺气肿对气雾剂沉积的影响。这项拟议研究中开发的技术还将使未来对众多不同肺部疾病模型的MRI研究成为可能。

DESCRIPTION (provided by applicant): Detailed knowledge of the fate of aerosols in the lung is essential in understanding the effect of exposure to airborne particulate matter (PM) and infectious agents as well as in assessing the efficacy of inhaled drug therapy. Detailed yet non-invasive studies of peripheral aerosol deposition (DE) are almost impossible in humans. Thus, understanding the fate of aerosols in the lung requires the use of animal models in which more invasive techniques can be used and/or computational models. In the last decade, Magnetic Resonance Imaging (MRI) has become a major imaging modality both in clinical medicine and in life science research, and has been successfully used in various lung studies. Recently it has also been shown that, using MRI scanners with very high spatial resolutions (50-100 5m), it is possible to directly measure the location of single micron-sized particles of iron oxide in tissue. The two main objectives of the study are 1) to improve our MRI technique to measure aerosol DE patterns in a rat model; and 2) apply this technique to characterize the effects of emphysema on aerosol DE patterns. We will first deliver aerosolized fluorescent-labeled iron oxide particles to healthy anesthetized rats. Using high-resolution MRI, we will characterize the aerosol DE patterns for the entire rat lung and determine the relative DE in subregions of the lung varying in size from lobar to sub-lobar. We will also characterize the aerosol DE patterns in the same animals by fluorometry to validate the MRI data. Using this novel MRI technique, we will then study the effect of emphysema on aerosol DE. Six weeks prior to aerosol exposure, emphysema will be induced in Wistar rats by intratracheal instillation of pancreatic elastase. Healthy and emphysematous rats will then be tracheally ventilated with aerosolized iron oxide particles (1 and 3 micron) under controlled breathing patterns. Animals will be imaged by MRI to produce regional maps of aerosol DE. The effect of emphysema will be determined by analysis of coefficients of variation and by comparison between DE maps obtained in healthy and emphysematous rats. The proposed study, that will provide a detailed quantitative description of aerosol DE patterns in the lung, is relevant to three main areas: 1) exposure to airborne PM, 2) the disease of emphysema and 3) the improvement of therapy by aerosol inhalation. There is ongoing growing evidence that exposure to ambient PM increases cardiopulmonary morbidity and mortality in susceptible subpopulations. Knowledge of the DE patterns of particles will not only provide quantitative assessment of aerosol DE but also insightful information for the characterization of host immune responses resulting for PM exposure. A better understanding of the fate of aerosols in the lung will also be beneficial in aerosol drug therapy as it will allow for better targeting of the drugs to their intended site of action. Finally, emphysema, one of the most common chronic illnesses of the population over 45 years of age, alters pulmonary gas flow and therefore the penetration and subsequent DE of inhaled particles in the lung. The validation of the MRI technique will provide an important tool in elucidating the effect of emphysema on aerosol DE. Such validation will also enable future MRI studies of numerous different lung disease models. Project Narrative: We propose to quantitatively assess by Magnetic Resonance Imaging (MRI) the distribution of deposited particles resulting from aerosol exposure in a rat lung. The proposed research is relevant to public health as 1) it will provide insightful information for the characterization of host immune responses resulting for particulate matter exposure, 2) will be beneficial in aerosol drug therapy as it will allow for better targeting of the drugs to desired regions of the lung and 3) will elucidate the effect of emphysema on aerosol deposition. The technique developed in the proposed research will also enable future MRI studies of numerous different lung disease models.