Airspace Surface Chemistry Mediates O3-Induced Lung Injury

Abstract

Ozone (O3) produces diverse pulmonary pathophysiologies but with marked heterogeneities relative to species, age, anatomic site, disease, and exposure history. These pronounced susceptibility variations have remained largely undefined. We have postulated that interactions between inhaled O3 and the airspace surfaces appreciably govern the distribution and extent of lung injury. O3 displays unique absorption properties wherein chemical reaction with the epithelial lining fluid (ELF) maintains the net flux from the gas phase and couples O3 uptake with the generation of products that lead to cell injury. Diversities in respiratory tract geometry and interfacial physicochemical conditions leads to spatially heterogeneous rates of O3 flux into the ELF which combine with the local production of bioactive species to dictate the local dose. We have observed that both the uptake and distribution of acute epithelial injury is principally localized to the conducting airways. O3 preferentially reacts with ELF ascorbic (AH2) and uric acids (UA) although reaction with GSH and unsaturated fatty acids (UFA) occur to a lesser extent. UFA reactions may not generate sufficient bioactive materials to account for acute cell injury. Reactions with AH2 and GSH, but not UA or Trolox, form secondary oxidants that initiate oxidation of model membranes and in vitro cell damage. However, secondary oxidant production is antioxidant concentration-dependent with a hyperbolic-shaped dose/response curve. Acquisition of species-specific data characterizing the pharmacodynamics of ELF substrate turnover under both basal and exposure conditions are critical to further our understanding of how surface chemistry regulates the balance between quenching of inhaled O3 and conditions that promote production of bioactive/cytotoxic species and, therefore, biological outcomes.