Air pollution is a significant cause of respiratory disease, and the most common gaseous air pollutants are ozone (O3), sulfur dioxide (SO2) and nitrogen dioxide (NO2). The primary goal of this study is to elucidate cellular mechanisms by which these gaseous air pollutants damage nasal and bronchial epithelial cells and promote inflammation in these tissues. Previous research suggests that these epithelia play an active role in the processes of health and disease through the synthesis of cytokines (protein mediators) and the expression of additional molecules which function as cell-cell, cell-substratum and cell-leukocyte adhesion receptors. The overall hypothesis of this proposal is that air pollutants act directly on the membranes of airway epithelial cells and, as a consequence, modulate adhesion receptor expression and cytokine production. An in vitro cell culture approach is proposed which will examine the responses of human and nonhuman primate nasal and bronchial epithelial cells. Both primary cell cultures and cell lines will be used. The first goal is to define the synthesis and expression of the cell-cell and cell- substratum receptors by these cells. These include proteoglycans, CD44, CD26, and beta1 integrins. Constitutive production of these receptors will be examined as well as changes caused by exposure to O3, SO2 and NO2. Exposures to individual gases and gases in combination will be done at ambient or near ambient concentrations (O3, 0.1-0.5 ppm; SO2: 0.5-5 ppm; NO2: 0.1-0.5 ppm). The hypotheses being tested are that respiratory epithelial cells produce adhesion molecules necessary to maintain normal epithelial function and that exposure to gaseous pollutants alter the synthesis of these products, adversely affecting tissue integrity. The second goal is to measure the expression of intercellular adhesion molecule-1 (ICAM-1) on nasal and bronchial cells and the effects of exposure to O3, SO2 and NO2 on the expression of this receptor. ICAM-1 is the primary leukocyte adhesion receptor on epithelial cells. The hypothesis being examined is that exposure to gaseous pollutants upregulates epithelial cell ICAM-1 expression thus enhancing the local inflammatory response by promoting leukocyte-epithelial adhesion. The third goal is to examine the types of cytokines produced by nasal and bronchial epithelial cells, and if the qualitative and quantitative synthesis of these cytokines is altered by exposure to O3, SO2, and NO2. The hypotheses being examined are that respiratory epithelial cells produce soluble factors which promote local inflammation and that exposure to pollutants stimulates these events. This study will advance our understanding of the functions of respiratory epithelial cells in maintaining normal tissue integrity and will determine whether gaseous pollutants produce respiratory inflammation and damage by modulating cytokine and adhesion receptor synthesis.
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