Chronic bronchial asthma is characterized by inflammation, increased airway smooth muscle tone, mucus hypersecretion and mucosal edema. Challenge of some allergic sheep with Ascaris suum antigen causes an acute bronchoconstriction followed by a late phase bronchial obstruction (dual responders) while only an acute bronchoconstriction occurs in other sheep (acute responders). Changes in bronchial blood flow (Qbr) may contribute to the pathogenesis of early and late phase airway responses by affecting mediator clearance and/or mucosal edema formation. In preliminary studies using open chested sheep, Qbr was monitored using a non-cannulating electromagnetic flow probe along with pulmonary mechanics and systemic and pulmonary hemodynamics, and the effects of Ascaris suum were characterized in acute and dual responders. These experiments showed that early phase antigen-induced bronchoconstriction occurs concomitant with an increase in Qbr in acute and dual responders and that late phase bronchial obstruction in dual responders was preceded by an increase in Qbr. The proposed studies will evaluate neural influences and the influence of mediators released or generated by antigen challenge on Qbr. Furthermore, the relative contributions of antigen-induced changes in pulmonary mechanics and pulmonary and systemic hemodynamics on Qbr will be compared to changes produced by local mediator release. Putative mediators of antigen-induced increases in Qbr include histamine, slow reacting substance of anaphylaxis, cyclooxygenase and lipoxygenase products of arachidonic acid metabolism, and altered neural influences.
The specific aims of this proposal are to: 1) characterize early and late phase changes in Qbr after antigen challenge in acute and dual responders; 2) show that similar responses on Qbr are evoked by non-immunologic degranulation of mast cells with compound 48/80; 3) demonstrate the requirement for airway mast cell degranulation in antigen induced changes of Qbr by pretreatment with cromolyn sodium; 4) evaluate the relative contribution of lipoxygenase and cyclooxygenase products to antigen-induced changes in Qbr by treatment with pharmacologic agents; 5) assess the role of cholinergic and adrenergic influences in early and late increases in Qbr; and 6) demonstrate that dual phase increases in Qbr can be evoked by challenge with specific mediators. These studies will better define the role of the bronchial circulation in asthma and may establish a basis for new and improved therapies.
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