Ozone induces toxic damage to the lung at a small but specific site, the alveolar region most proximal to the terminal bronchiole. Distal alveoli are spared, thus suggesting the presence of either a decreasing O3 dose gradient within the alveolar region or a difference in cellular susceptibility. Because of resolution limitations no experimental studies have ever demonstrated the alveolar region dose gradient. The final dose that reaches this proximal alveolar region is regulated by 03 uptake within the nasopharynx and tracheobronchial tree. Using radioactive and stable oxygen isotopes as 03 dosimetry tracers we will test the hypothesis that a significant alveolar region dose gradient exists causing the proximal region to absorb substantially more 03 than the distal region, and that the nasopharynx acts as a major determinate of alveolar 03 uptake. Oxygen-l5 labeled 03 (15-OOO) will be generated using a cyclotron, and laboratory animals will be given an acute exposure. The radioactivity of major tissues such as the nasopharynx, trachea, individual lung lobes, and extra-pulmonary tissues will be measured using a gamma-ray counter. Intraspecies comparisons in rats and interspecies comparisons between mice, hamsters, rats, and guinea pigs will be examined for 03 deposition differences. Mechanical ventilation will be used to investigate the effect of ventilatory parameter alteration on dosimetry. The elution profile of 15-OOO reaction products from the trachea will be assessed for those products which stay within the airway because they are unable to diffuse in aqueous media. The lipid vs. non-lipid components of 15-OOO reaction products in bronchoalveolar lavage fluid will be measured. The major functional compartments containing 03 reaction products such as lipid vs. non-lipid and aqueous soluble vs. non-soluble whole lung will be analyzed using 18-O3. The 18-O3 will be analyzed using Charged Particle Activation Analysis (CPAA) where the oxygen-18 is converted to fluorine-18, a radioisotope which decays by positron release. CPAA followed by positron - track autoradiography will be used to demonstrate and quantify 18-O3 gradients within the alveolar region of lung sections. This proposed investigation will provide an experimentally-based analysis of 03 dosimetry throughout the respiratory tract.
| Dunn, W L; Russell, M L; Wieland, B W et al. (1997) Monte Carlo analysis of multi-layer targets for production of 15O. Appl Radiat Isot 48:1591-600 |
| Mercer, R R; Russell, M L; Crapo, J D (1994) Alveolar septal structure in different species. J Appl Physiol 77:1060-6 |
