The goal of this project is to understand how inflammation induced by the inhalation of bacterial endotoxin affects the response of the airway epithelium to ozone, the principal oxidant air pollutant in photochemical smog. Each toxicant alone causes airway inflammation that is followed by mucous cell metaplasia characterized by proliferation of mucus-secreting cells in regions of the airway that normally contain no or few secretory cells. Mucous cell metaplasia is a common pathologic feature of airway diseases, such as chronic bronchitis, cystic fibrosis, and asthma. The consequences of co-exposure to these two airborne pollutants have not been fully explored. These studies will focus on the effects of co-exposure on the pathogenesis of: 1) the initial epithelial cell injury and inflammation, and 2) the subsequent induction of mucous cell metaplasia associated with mucin synthesis and secretion. Experiments will extend preliminary findings indicating that co-exposure of rats to endotoxin and ozone will induce greater premetaplastic lesions (airway inflammation and epithelial cell loss) than exposure to either toxicant alone. Studies will determine if the magnitude of the premetaplastic epithelial lesions is dependent on the initial inflammatory cell response. Studies will also focus on the pathogenesis and severity of the mucous cell metaplasia caused by co-exposure to ozone and endotoxin by determination of nasal and bronchial airways epithelial differentiation, increased mucin mRNA, hypersecretion of mucins. The role of ozone/endotoxin-induced inflammatory cell response in the overproduction of airway mucus will be examined. A combination of morphometric, histochemical, immunochemical, and molecular techniques will be used to identify temporal alterations in epithelial cell populations, intraepithelial mucosubstances, mucin gene expression, and mucin secretion in nasal and pulmonary airways. The results from these studies will reveal interactive effects of co-exposure on the mucous apparatus of the nasal and pulmonary airway epithelium, and the role of neutrophils in the amplification of airway alterations due to co-exposure to ozone and endotoxin.
