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 onthe developing lung. Responses to a given exposure demonstrate marked heterogeneity with respect toage, anatomic site, species, and exposure history. Infants may be particularly at risk due to a greaterinhaled 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 smallmolecular 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 injuriouseffect of inhaled O3. Nonetheless, compelling evidence suggests that reactions between O3 and ELFantioxidants and lipids are critical to exposure-related cellular effects. Due to the unique absorptionproperties of O3, the endogenous pools and regulation of the ELF will dictate the profile of bioactive speciesgenerated 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 theextracellular chemistry occurring between O3 and constituents of the epithelial lining fluid. As partof 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 dosegeneration. 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 pulmonarycompartments, the surface chemistry and product formation that occur during exposure; AH2 dynamics inthe ELF; antioxidant profiles in both nasal/lung ELF and site-specific tissues, the spatial distribution of thelocal 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 rhesusmonkey and rat models. These characterizations will continue to provide key new insights regarding themechanisms of differential susceptibility, how surface phenomena govern the impact of exposure in thedeveloping lung, and the utility of the nose to serve as a sentinel for the lung. It is anticipated that theseefforts will extend into translational human studies. The project will facilitate the program as a whole bydirectly interacting with Projects 2 & 3 in correlating surface chemistry to cellular responses, Project 4 in thebuilding and validation of predictive models, and will rely on Core B for exposure protocols and Core C forthe robust statistical analyses that will document causalitv and the efficacv of the nose as a sentinel.
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