When relaxation responses to intraluminal hyperosmolarity, i.e., EpDRF-mediated responses, were inhibited Fedan et al., 2000 ; . In that study, reactivity to MCh and hyperosmolar solution eventually returned to normal in the face of substantial morphological changes in the epithelium. In the present study, we observed that KCl-evoked, EpDRF-mediated responses were unaffected by 3 mM diacetyl, even though sensitivity to MCh was increased. Thus, diacetyl treatment had not interfered with the release and or effects of EpDRF at a time when reactivity to MCh was increased. That is, the epithelial cells were not impaired to the degree that the direct, contractile effect of KCl on the smooth muscle overwhelmed the relaxant effect of released EpDRF. Diacetyl depolarized the epithelium substantially and reduced Rt, and, in one preparation, abolished Rt. The greater change in Vt than Rt suggests that diacetyl inhibited ion transport across the epithelium. The transport pathway s ; involved in these electrophysiological responses will need to be established in future experiments. The decrease in Rt may reflect a generalized permeability increase across the epithelium which may be of sufficient magnitude to contribute to the increased reactivity to intraluminal MCh. Whereas workers are exposed by inhalation to popcorn flavoring vapor, our experiments on the in vitro effects of diacetyl have examined the effects of diacetyl in solution, which is an artificial exposure system. The concentrations of diacetyl that are achieved in airway surface liquid in workers have not been described, and it is difficult to extrapolate our current findings to the work site hazard. However, having established that diacetyl in solution alters airway epithelial function, our future experiments using delivery of diacetyl vapor in vitro will determine the vapor concentrations that produce an effect on epithelium and may allow us to compare these effects with those described in this report. In conclusion, our results suggest that diacetyl exerts toxic effects on airway epithelium, which lead to airway hyperreactivity in vitro and degradation of its protective barrier function. The specific pathways involved in diacetyl's effects on epithelium require additional study. However, it is clear that the agent has untoward effects on epithelial cells under conditions in which inflammatory cells were not available from the blood. Mediators from resident inflammatory cells, which are limited in number in the airways from untreated animals, are not likely to have elicited the changes that were observed. The effects of diacetyl observed in this study may represent early functional changes in the epithelium in the airways of exposed workers.
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