Lipid mediators released from inflammatory cells have potent effects on airway function, and could play an important role both in allergic reactions in human airways and in chronic asthma. We propose studies 1) to characterize the allergen stimulated release of lipid mediators into the intrapulmonary airways of man 2) to determine the effects of selective enzyme inhibition by pharmacologic agents on eicosanoid formation and 3) to examine the alteration of the airway responses to allergen by agents that alter synthesis of eicosanoids or antagonize their effects. We will more fully characterize the release of lipid mediators, especially PGD2, its principle metabolite, 9 alpha 11 beta-PGF2, TxA2 and platelet activating factor, into bronchoalveolar lavage (BAL) fluid of allergen challenged human lung. Mediators which might be responsible for the airway inflammation and increased airway reactivity characteristic of the late asthmatic response (LAR) will be sought in BAL from allergic asthmatics during the transition phase from acute allergen-induced bronchoconstriction to LAR. New assays for plasma methyl histamine and the principle urinary metabolite of PGD2 will permit us to study eicosanoid biosynthesis in vivo by mast cells and basophils during the LAR. We have shown increased formation of lipoxygenase products after pulmonary allergen challenge in the presence of cyclooxygenase inhibitors in sheep and will examine the possibility of diversion of products to the lipoxygenase pathway by cyclooxygenase inhibition in man. The biochemical and functional consequences of thromboxane synthase inhibition will be assessed both following allergen inhalation and in chronic symptomatic asthma. The contribution of bronchoconstrictor prostaglandins to early and late phase allergic bronchoconstriction will also be investigated using a potent receptor antagonist for constrictor prostaglandins. Testing the effect of lipoxygenase inhibition on mediator release in challenged lung will be done in the sheep, in tandem with studies on the effect of combined lipoxygenase and cyclooxygenase inhibition on allergic bronchoconstriction in sheep. These studies will expand our understanding of the role of lipid mediators in IgE-mediated pulmonary disorders and in asthma.

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National Institute of General Medical Sciences (NIGMS)
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Vanderbilt University Medical Center
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