MECHANISMS OF AIR POLLUTANT-INDUCED AIRWAY PERMEABILITY

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Air pollutants are known to disrupt the epithelial barrier and increase the mucosal permeability of the airwaves, but the cellular mechanisms involved in producing these effects are far from clear. The proposed studies extend our previous work and represent an in-depth analysis of the interrelationships among cytoskeletal components, inflammatory events, and epithelial changes elicited by ozone (O3) as the prototypical oxidant air pollutant. Since the cellular responses after O3, exposure may be transient, a time course analysis of permeability, inflammatory, and structural changes will be done in rats exposed acutely to clean air, 0.1 ppm, 0.2 ppm, 0.5 ppm, and 1.0 ppm 03. The tim sequence of effects produced by acute exposure will be compared to the effects of subchronic (4 week) and chronic (9 months) exposures st comparable interactions with endothelial and epithelial cells prior to cellular injury, polymorphonuclear leukocytes (PMNs) and macrophage from 03-exposed rats will be studied for (i) adhesion of PMNs and macrophage to endothelial and epithelial cells in culture, (ii) changes in cell adhesion molecules, (iii) changes in cytoskeletal components associated with PMN stimulation and motility, (iv) disruption of tight junctions and cytoskeletal components of epithelia, and (v) release cellular mediators, i.e., prostaglandin E2 (PGE2), leukotriene B4 (LTB4) and a cell adherence promoter (TNF). To reverse the O3 effects, the cells will be treated with the inhibitors of PGE2 and LTB4 (indomethacin and FPL55712), antioxidant (catalase), and antibodies to TNF and IL1. Extension of in vitro studies to an in vivo setting will involve exposure of rats to O3 and detection of (i) marginating PMNs in lung capillaries, (ii) expression of IL1 and TNF in epithelial cells and macrophage and (iii) prevention of O3 effect by antibodies to TNF or IL1, or by PMNs treated with these antibodies. This project offers a coherent toxicologic and mechanistic approach for an understanding of the impact of oxidant air pollutants on the respiratory system and serves to fill some critical gaps in the existing literature.