Toxic inhaled particles can initiate or aggravate pulmonary disease, and drugs for treatment of lung diseases can be used effectively by inhalation. Our research objectives are to identify and to understand the determinants of inhaled particle deposition sites in the lungs as well as the sites of subsequent redistribution and clearance. In the past, we described particle deposition patterns by autoradiography of lung slices and by quantifying the amount of radioactivity in small pieces of lung. This provided more sensitive measurements of deposition patterns than external imaging methods and provided a means for correlating retention patterns which pathologic changes. However, it was not sensitive enough to precisely localize and quantify particles in structures of the lung parenchyma. Therefore, with this proposal, we use new approaches to examine particle deposition sites in the lungs and quantify local particle concentration as a function of lung microanatomy, particle size, and breathing pattern. Morphometric methods will be used to determine the numerical density of 0.9, 1.8, and 3.0 um fluorescent latex particles deposited in bronchioles, alveolar ducts, and alveoli in normal lungs. These studies will first be done in spontaneously breathing animals whose breathing pattern is monitored and recorded. This breathing pattern as well as altered breathing patterns will then be imposed upon both in situ ventilated and excised ventilated animal lungs and deposition patterns compared. We will then study deposition patterns in excised human lungs obtained at post mortem examination. Using the human lungs, we will also vary both particle size and breathing pattern to provide human deposition data at a level of anatomical resolution far beyond any previous study. We will also use our methods to investigate pathways of clearance in normal animal lungs. Our hypothesis is that clearance pathways and rates are dependent on the initial deposition site. The information gained from these studies should help identify both the mechanisms important in regional deposition, and the pathways of redistribution and clearance relevant to environmental and therapeutic aerosols.
