Project 1 - Biochemical Determinants of Local Dose Govern O3 Toxicity

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Ozone (O3) remains an important public health problem especially with regards to sensitive populations. Numerous recent studies document that exposures induce both short and potentially long term impacts on the developing lung. Responses to a given exposure demonstrate marked heterogeneity with respect to age, anatomic site, species, and exposure history. Infants may be particularly at risk due to a greater inhaled dose rate. Respiratory tract surfaces are covered by an aqueous layer (epithelial lining fluid; ELF) that inhaled gases first encounter and is a complex mixture containing significant concentrations of small molecular weight antioxidants (e.g., ascorbic acid (AH2), glutathione, and uric acid), lipids, and proteins. The standard paradigm proposes that ELF antioxidants provide a protective screen against the injurious effect of inhaled O3. Nonetheless, compelling evidence suggests that reactions between O3 and ELF antioxidants and lipids are critical to exposure-related cellular effects. Due to the unique absorption properties of O3, the endogenous pools and regulation of the ELF will dictate the profile of bioactive species generated during exposure. In this renewal application we hypothesize that the spatial distribution, magnitude, and temporal pattern of biological responses to O3 exposure are dependent on the extracellular chemistry occurring between O3 and constituents of the epithelial lining fluid. As part of the overall Program Project, Project 1 will characterize how surface interactions influence the local dose. Surface chemistry, dictated by ELF homeostasis and local O3 flux rates, governs the rate of local dose generation. Building upon advancements in this project and the program at large over its first two years, this hypothesis will be addressed by four specific aims that will characterize, in nasal and pulmonary compartments, the surface chemistry and product formation that occur during exposure; AH2 dynamics in the ELF; antioxidant profiles in both nasal/lung ELF and site-specific tissues, the spatial distribution of the local dose; and the contribution of the local dose to the expression of pathology across animal age, exposure pattern (acute vs. episodic), exposure history, and post-recovery challenge in both our rhesus monkey and rat models. These characterizations will continue to provide key new insights regarding the mechanisms of differential susceptibility, how surface phenomena govern the impact of exposure in the developing lung, and the utility of the nose to serve as a sentinel for the lung. It is anticipated that these efforts will extend into translational human studies. The project will facilitate the program as a whole by directly interacting with Projects 2 & 3 in correlating surface chemistry to cellular responses, Project 4 in the building and validation of predictive models, and will rely on Core B for exposure protocols and Core C for the robust statistical analyses that will document causalitv and the efficacv of the nose as a sentinel.