Project 1 - Biochemical Determinants of Local Dose Govern O3 Toxicity

University Of Alabama At Birmingham, Birmingham AL

Investigators

Linked publications, trials & patents

Abstract

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