This application is part of a long-term effort to determine the relationship(s) between airway inflammation and airway hyperresponsiveness, a central feature of asthma. The proposed experiments will focus on the role of tachykinins, a class of low molecular weight peptides that are present in the airways of several mammals, including humans. Tachykinins play an important role in several inflammatory processes and have recently been found to be required for the induction of airway hyperresponsiveness by toluene diisocyanate (TDI), a widely used chemical that is a well known cause of occupational asthma. TDI exposure also potentiates the effects of exogenously administered tachykinins, at least in part by inhibition of neutral endopeptidase, an enzyme that contributes to local tachykinin metabolism. In the proposed experiments, we will first determine whether stimuli known to induce release of tachykinins into the airways can themselves induce airway hyperresponsiveness in guinea pigs, and whether this effect requires simultaneous inhibition of neutral endopeptidase. In similar experiments we will evaluate the effects of exogenous administration of specific tachykinins. Next we will determine whether tachykinins contribute to the increase in airway responsiveness caused by two other inflammatory stimuli, ozone and inhaled antigen, by evaluating the effects of tachykinin antagonists, tachykinin depletion and neutral endopeptidase inhibition on these responses. We will also determine whether these stimuli, like TDI, themselves lead to inhibition of airway neutral endopeptidase activity. To determine the mechanisms by which tachykinins contribute to airway hyperresponsiveness we will evaluate the effects of tachykinins and of TDI in augmenting acetylcholine release from efferent nerves and in increasing airway epithelial permeability. We will also evaluate the role of platelet activating factor in these responses. In addition, we will evaluate the mechanisms by which TDI inhibits airway neutral endopeptidase activity, by evaluating the effects of TDI on purified neutral endopeptidase and on neutral endopeptidase activity in tracheal explants. In these experiments we will focus on possible roles of toxic oxygen metabolites and proteolytic enzymes in inactivating neutral endopeptidase. Finally, we will pursue any positive in vitro experiments with studies of neutral endopeptidase inactivation by in vivo exposure of guinea pigs to TDI. These experiments will help to clarify the role of an important class of inflammatory mediators (tachykinins) in the induction of airway hyperresponsiveness and will also further our understanding of the links between hyperresponsiveness and inflammation.
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