Mechanisms of Species-Dependent Environmental Lung Injury

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This is the first competing renewal of a program project initially funded for three years starting in June 2003. The fundamental goals and innovative structural paradigm of this multi-institution, multi-investigator program remain essentially unchanged. Approximately half of the US population continues to be impacted by pathogenic air pollutants such as ozone (O3), which recent epidemiologic studies suggest induces long term functional impairments in children. Despite extensive research endeavors, the mechanisms of exposure-related lung injury and how age and exposure history govern acute and chronic susceptibility in the post natal lung remain poorly understood. Novel evidence documents that postnatal, episodic O3 exposure profoundly alters lung growth, structure, and function in non-human primates. Biological effects are likely determined by the combination of O3 intrapulmonary dispersion and reaction/diffusion within the epithelial lining fluid (ELF), leading to generation of the local dose. Thus, we hypothesize that the age-, site-, cell-, and exposure history-related susceptibilities to acute versus episodic O3 result from differences in ELF-dependent interactions associated with spatial heterogeneities in the local dose coupled with differential regulation of the airway epithelial intracellular and ELFantioxidant pools. In lieu of our originally proposed airway sensitization component, we have prioritized our current goals to focus on age, biological variation, and exposure history (including recovery) related susceptibilities. Our efforts will advance understanding of the fundamental mechanisms of O3-related disruption of normal lung development, lung injury, and susceptibility; and generate unique characterizations of lung structure and biochemistry. The interdisciplinary research team encompasses expertise in lung surface chemistry, pathobiology and quantitative morphology, imaging and 3-dimensional reconstruction, dosimetry, extrapolation modeling, and biostatistics. This highly interactive program will utilize non-human primates (rhesus monkeys) and, to expand our database, rats, and encompasses interdependent projects (4) and cores (3). We intend to characterize the ELF-mediated local dose generation; define the mechanisms of postnatal susceptibility; characterize airway response determinants as a function of acute vs episodic exposures; develop lung injury biomarkers utilizing the nose as a sentinel; build structural atlases extracted from 3-D reconstructions, and, formulate models that predict health outcomes. The program spans from molecular interactions to the intact primate, is highly relevant to NIEHS goals, is anticipated to extend into the human population, and will substantially reduce the uncertainties regarding the health effects of oxidant air pollution in our childhood population.