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.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
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Toxicology Subcommittee 2 (TOX)
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University of California Irvine
Public Health & Prev Medicine
Schools of Medicine
United States
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Mautz, W J; Kleinman, M T; Bhalla, D K et al. (2001) Respiratory tract responses to repeated inhalation of an oxidant and acid gas-particle air pollutant mixture. Toxicol Sci 61:331-41
Bhalla, D K; Gupta, S K (2000) Lung injury, inflammation, and inflammatory stimuli in rats exposed to ozone. J Toxicol Environ Health A 59:211-28
Bhalla, D K; Gupta, S K; Reinhart, P G (1999) Alteration of epithelial integrity, alkaline phosphatase activity, and fibronectin expression in lungs of rats exposed to ozone. J Toxicol Environ Health A 57:329-43
Reinhart, P G; Gupta, S K; Bhalla, D K (1999) Attenuation of ozone-induced lung injury by interleukin-10. Toxicol Lett 110:35-42
Bhalla, D K (1999) Ozone-induced lung inflammation and mucosal barrier disruption: toxicology, mechanisms, and implications. J Toxicol Environ Health B Crit Rev 2:31-86
Reinhart, P G; Bassett, D J; Bhalla, D K (1998) The influence of polymorphonuclear leukocytes on altered pulmonary epithelial permeability during ozone exposure. Toxicology 127:17-28
Gupta, S K; Reinhart, P G; Bhalla, D K (1998) Enhancement of fibronectin expression in rat lung by ozone and an inflammatory stimulus. Am J Physiol 275:L330-5
Pearson, A C; Bhalla, D K (1997) Effects of ozone on macrophage adhesion in vitro and epithelial and inflammatory responses in vivo: the role of cytokines. J Toxicol Environ Health 50:143-57
Bhalla, D K; Hoffman, L A; Pearson, A C (1996) Modification of macrophage adhesion by ozone: role of cytokines and cell adhesion molecules. Ann N Y Acad Sci 796:38-46
Bhalla, D K (1996) Alteration of alveolar macrophage chemotaxis, cell adhesion, and cell adhesion molecules following ozone exposure of rats. J Cell Physiol 169:429-38

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