Pulmonary epithelial cells are constantly exposed to a diverse array of oxidants. Cellular injury occurs when the oxidant burden exceeds defense mechanisms. Oxidant stress induces an exposure-dependent, temporal """"""""adaptation"""""""" during which responses are attenuated. The attenuation cannot be solely explained by augmented intracellular antioxidants. The lung surfaces are covered by a surface lining layer (SLL) which is the first compartment inhaled oxidants contact and, into which endogenously- derived oxidants (eg., """"""""NO, H2O2) are secreted by resident epithelial and inflammatory cells. Based on the unique absorption properties of nitrogen dioxide (NO2) and ozone (O3), we hypothesize that within the SLL, the initial events between extraCellular (EG) oxidants and SLL constituents are critical to the mechanisms of toxiCity induction and extent of epithelial injury. NO2 and O3 are reactive oxidant gases that are absorbed due to chemical reactions within the SLL which (a) directly couples absorption-based disappearance of the parent oxidant with production of SLL-derived reaction products and, (b) localizes the primary oxidative events to the EC space. Thus, heterogeneities in SLL constituent profiles, either inherent or exposure-induced, will govern the extent of injury produced by inhaled or endogenous EC oxidants. We propose that the SLL contributions to the governance of oxidant lung injury have been largely ignored. Employing NO2 and O3 as model EC oxidants, our hypothesis will be addressed by interrelated experimental aims utilizing tightly controlled models which span from kinetic analysis of SLL reactants, to biochemical and cellular constructs mimicking the lung surface, to whole animal exposure models. Accomplishment of the proposed aims will: 1) delineate the SLL primary targets and their contribution to initiating exposure-induced cell injury, 2) characterize the SLL constituent conditions that either amplify or quench pulmonary epithelial injury from EC oxidants, and 3) quantify the contribution of the SLL to both the development (and loss) of adaptation and to intrinsic host susceptibility to EC oxidants. These proposed experiments will reveal new information regarding the mechanisms which govern the pathogenesis of oxidant lung injury especially as related to the origin of the adaptive response, the basis of differential susceptibilities, and the potential to ameliorate lung injury.
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