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.
