Academic journal article Environmental Health Perspectives

The Role of Inflammatory Mediators in the Synergistic Toxicity of Ozone and 1-Nitronaphthalene in Rat Airways

Academic journal article Environmental Health Perspectives

The Role of Inflammatory Mediators in the Synergistic Toxicity of Ozone and 1-Nitronaphthalene in Rat Airways

Article excerpt

Ambient air is polluted with a mixture of pulmonary toxicants. Previous studies indicate that prior exposure to atmospheric oxidant pollutants such as ozone may significantly alter the response to other pollutants, such as 1-nitronaphthalene (1-NN). 1-NN, a component of the particulate exhaust from diesel engines, has been found at low concentrations in ambient air. Using a metabolomic approach, we investigated inflammatory responses in arachidonic and linoleic acid biochemical cascades (35 metabolites) and the expression of 19 cytokines/chemokines at three time points (2, 6, and 24 hr) following exposure to 1-NN with and without prior long-term [O.sub.3] exposure. Long-term [O.sub.3] exposure is associated with biochemical changes that have been shown to render the lung resistant to further [O.sub.3] exposure. This study indicates that airways of [O.sub.3]-tolerant rats exhibited a low level of chronic inflammation, rendering the lungs more susceptible to other environmental pollutants such as 1-NN. Specifically, a 12.5-mg/kg dose of 1-NN to [O.sub.3]-tolerant rats produced significantly higher levels of cysteinyl-leukotrienes in bronchiolar lavage fluid even when compared to a 50-mg/kg dose of 1-NN in rats exposed to filtered air. Collectively, these results indicate that the combination of exposures as encountered in polluted ambient air are considerably more injurious to the lung than would be anticipated from previous studies employing single exposures. The observed synergism between [O.sub.3] and 1-NN may be causally related to a shift in a T-helper 1 to T-helper 2 immune response in the airways. Key words: 1-nitronaphthalene, arachidonic acid, cyclooxygenase, inflammatory mediators, linoleic acid, lipoxygenase, ozone. Environ Health Perspect 114:1354-1360 (2006). doi:10.1289/ehp.8373 available via http://dx.doi.org/ [Online 22 June 2006]

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Human epidemiologic studies have shown a relationship between ozone exposure and a decrease in pulmonary function in both children and adults (Balmes et al. 1997; Gauderman et al. 2004; Hiltermann et al. 1998). [O.sub.3] is produced through photochemical reactions of volatile organic compounds in the presence of nitrogen oxides and sunlight. Exposure to [O.sub.3] occurs primarily through inhalation, and causes injury and alterations to the respiratory tract. The National Ambient Air Quality Standard for [O.sub.3] is set at 0.12 ppm [U.S. Environmental Protection Agency (EPA) 2000], which is often exceeded in urban areas during the summer months. Inhaled [O.sub.3] first reacts with constituents of the epithelial lining fluid (e.g., micronutrient antioxidants such as ascorbate, urate, and vitamin E) and unsaturated lipids by reactive absorption.

[O.sub.3] reaction with these components of the epithelial lining fluid produces reactive products including highly reactive aldehydes, hydrogen peroxide, superoxide, oxysterols, and hydroxyl radicals (Connor et al. 2004; Pulfer et al. 2005; Putman et al. 1997). Therefore, cellular responses to [O.sub.3] are rarely a result of the direct reaction of [O.sub.3] with cell surface components, but are rather mediated through a cascade of secondary products (Kelly et al. 1995; Pryor 1994). The lung's inflammatory cells, such as macrophages, eosinophils, and neutrophils, constitute a major component of this cascade. Upon activation, these cells generate reactive oxygen and nitrogen species and cause substantial injury to lipid membranes, intracellular components, and proteins. In addition, [O.sub.3] exposure activates epithelial cells and inflammatory cells to release cytokines, chemokines, and arachidonic acid. Arachidonic acid can be metabolized to leukotrienes (LTs), prostaglandins (PGs) hydroxyeicosatetraenoic acids (HETEs), dihydroxyeicosatetraenoic acids, and other metabolites.

Previous studies have examined acute [O.sub.3] exposure as it relates to changes in eicosanoid levels and other cellular mediators, such as chemokines, cytokines, fibronectin and cell adhesion molecules (Driscoll et al. …

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