The mechanisms underlying the pathogenesis of late responses to inhaled antigen are unknown but are clinically important because the same mechanisms may determine the severity of asthma in patients. During the previous grant period we studied two groups of sheep with airway hypersensitivity to inhaled Ascaris suum antigen: one group with only acute responses to antigen (acute responders) and one group with both acute and late responses to antigen (dual responders). These studies led to the hypothesis that dual responders release greater amounts of 5-lipoxygenase (5-LO) metabolites of arachidonic acid during the acute allergic reaction. This increase in 5-LO metabolites causes a more severe airway inflammatory response, characterized by neutrophils and eosinophils; these inflammatory cells then release mediators which contribute to the late response. We also found evidence that the mechanisms leading to late responses and those leading to antigen-induced airway hyperresponsiveness (AHR) develop in parallel but may be independent of each other.
The specific aims of the present proposal are to determine: 1) the site, composition, and time course of antigen-induced inflammatory cell influx into the airways after antigen challenge, and if modifying these parameters pharmacologically, affects the late response; 2) that airway anaphylaxis results in a sequential release of mediators which is an important determinant of late responses; 3) the airway and cellular responses to bronchoactive and/or inflammatory metabolites (i.e. leukotrienes, prostaglandins, and platelet activating factor) in both acute and dual responders and if differences in sensitivity and/or cell recruitment patterns to these agents are related to the different airway responses in these groups; and 4) the mechanisms involved in antigen-induced AHR, and if mechanisms leading to AHR differ from those of late responses. We will measure airway mechanics (in vivo), tracheal smooth muscle contraction (in vitro), cell differentials and mediator contents (by RIA and HPLC) in bronchoalveolar lavages, and mediator generation from isolated sheep granulocytes and from sheep whole blood. Lung morphology will be used to confirm airway inflammation and to document sites of leukocyte influx. The roles of suspected mediators will be defined by selective pharmacologic intervention. These studies will help identify the mechanism(s) of late responses and antigen-induced AHR, and thus, could provide the basis for introducing new, more specific and possibly more effective therapies for bronchial asthma.
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