Airway epithelial permeability is altered by airborne pollutants such as ozone and tobacco smoke. Despite the fact that such changes in permeability may be detrimental, the basic mechanisms that underlie this phenomenon are not well understood. In our previous mechanistic studies, ozone-induced changes in permeability, transport pathway and cytoskeleton were similar to changes induced by application of the microfilament destabilizing agent cytochalasin D. We now proposed to broaden this study by including an analysis of inflammatory cells, the products of inflammatory cells or epithelial cells, and various inhibitors of cell products as they relate to air pollutant effects on airway permeability, cytoskeleton, tight junctions and transport pathway. Inflammatory cells, upon activation, may aggregate in tracheal and alveolar mucosa and release products that modulate airway and vascular permeability and modify the cytoskeleton of cells in pulmonary endothelia or epithelia. A study of the cytoskeleton in combination with an investigation of epithelial cells, neutrophils, or their products, is therefore expected to improve our understanding of the mechanisms of permeability changes. The time sequence of increased permeability and duration in the tracheal and bronchoalveolar region will be studied, and permeability changes will be correlated with inflammatory response, cytoskeletal changes, tight junction alterations and structural pathways of tracer transport in the trachea and alveoli in: (1) rats exposed to air only or O3(O.6 ppm) or O3 (O.6 ppm) + NO2 (2.5 ppm), and (2) rats exposed to these gases and also treated with (a) oxidant products of neurotrophils (superoxide, hydrogen peroxide, hydroxyl radicals), (b) antioxidants (taurine, catalase, superoxide dismutase and dimethylthiourea, (c) anti- inflammatory drugs (mapacrine and methyl prednisolone), (d) products of arachidonic acid metabolism (leukotrienes and prostaglandins) or their inhibitors (FPL 55712, BW 755C and indomethacin), (e) cytoskeleton destabilizers and their combinations (colchicine, vinblastine ,cytochalasin D and colchicine + cytochalasin D). The role of neutrophils in airway permeability will also be assessed by studying permeability and inflammation following injection of isolated neutrophils into granulocytopenic unexposed or 03 expsoed inbred rats. Additional studies involving uptake of tracers by isolated alveolar type II cells, adherence of neutrophils to type II cells and cytoskeletal changes under conditions that alter in vivo permeability described above, will also be done to add to our understanding of the mechanisms of tracer transport.

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National Institute of Environmental Health Sciences (NIEHS)
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Toxicology Subcommittee 2 (TOX)
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University of California Irvine
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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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