Nitrogen dioxide (NO2), a highly toxic oxidizing gas, is encountered by a large segment of the population. The evidence for its toxicity is clearly established an involves a diverse spectrum of cellular and biochemical aspects both with the lung and possibly in extra pulmonary locations. However, the mechanisms by which it is absorbed from inspired air and how it exerts its broadly effective toxic action are poorly defined. NO2 is a relatively unique toxicant in that it exists as a reactive free radical but, probably due to limited aqueous interactions, is able to penetrate to distal airspaces upon inhalation. The reactions involved with its gas phase disappearance must be related to its mechanisms of toxicity. The proposed project is designed to delineate the determining factors and pathways involved in NO2 uptake, and to describe its interactions with pulmonary airspace surface and subsurface elements. In order to limit confounding factors and maximize exposure control, uptake will be studied utilizing an isolated perfused rat lung preparation. The effects of uptake of concentration, temperature, surface area, washout time, diluent gas content, and pharmacologic alteration of lung surface components will be determined. Direct intrapulmonary interactions of NO2 will be investigated via use of 15N labelled NO2 to trace NO2-N within the lung, and via infrared spectrometric direct gas phase NO2 analysis of reactions with pulmonary components contained in aqueous systems. Studies to determine the extent of surface versus subsurface interaction will include NO2 penetration through solute containing aqueous films, epithelial versus endothelial inhibition of bioactive peptide metabolizing enzymes, and use of Fourier Transform Infrared Spectrometry to investigate specific chemical alterations in surface and subsurface constituents. Where applicable, isolated cell studies will be incorporated to determine if NO2/cell interface interactions are uniform or if the lung airspace surface presents a unique situation due to its overlying material. Result will provide information necessary to define the pathways of uptake and initial toxic action. Such knowledge may then be incorporated into both descriptive models and improve basic understanding of the lung injury process, with potential for the establishment of protective interventions.
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