This proposal seeks to examine the adverse pulmonary effects associated with occupationally relevant exposure to low-molecular weight aldehydes. Occupational exposure to these compounds is extensive. Although the irritant properties of aldehydes are well documented, a clear understanding of the association between-these compounds and nonmalignant respiratory disease (e.g., asthma) is lacking. A principal reason for this is that the basic mechanisms by which these irritants induce pulmonary effects is uncertain. Thus, the overall purpose of this proposal is to investigate the effects of acrolein, a potent occupational aldehyde, at a cellular and subcellular level on an important target site, the airway epithelium. Specifically, this proposal seeks to investigate: 1. whether 8 hour acrolein exposure influences airway smooth muscle reactivity through alteration of the synthesis and release of mediators/enzymes present in the epithelium, and 2. whether the temporal pattern of acrolein-induced hyperreactivity coincides with epithelial damage and resolves with epithelial repair and the resolution of airway inflammation. To accomplish Objective 1, three experimental approaches will be employed that move from in vivo exposure to in vitro exposure. The first approach involves inhalation exposure of guinea pigs with subsequent removal of the trachea and determination of smooth muscle reactivity in vitro. Dose- response data obtained from this experiment will be used in subsequent tests. The second approach involves acrolein exposure of isolated tracheal segments in situ followed by evaluation of reactivity in vitro. The third approach involves direct in vitro exposure of guinea pig or human airway epithelial cells in culture and evaluation of conditioned medium on guinea pig smooth muscle reactivity. To accomplish Objective 2, the time course of the initiation and resolution of airway hyperreactivity will be examined in guinea pigs after acrolein exposure. Physiological (measurement of airway reactivity & enzyme activity) and morphological (cellular injury & steady-state mRNA levels) findings will be compared. The role of leukocytes in amplifying or prolonging hyperreactivity also will be examined by depressing circulating neutrophils by two agents--cyclophosphamide and hydroxyurea. The results from these tests will enable evaluation of in vivo and in vitro acrolein effects in the same species-guinea pig. In vitro data will be compared across species--human and guinea pig. Thus, in these studies we seek to evaluate the role of epithelial damage/repair and airway inflammation in aldehyde-induced airway hyperreactivity, a pathognomic feature of occupational asthma. These studies will provide new information on the underlying cellular mechanisms of respiratory toxicity for a significant class of irritant compounds, aldehydes.
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