MECHANISMS OF AIRWAY INFLAMMATION IN ASPIRIN INTOLERANT ASTHMA

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Aspirin-intolerant asthma is a clinical syndrome affecting 5-10% of the asthmatic population. Cyclooxygenase (COX) inhibitors, such as aspirin and indomethacin, stimulate release of large quantities of cysteinyl leukotrienes into bronchoalveolar lavage fluid (BALF) in aspirin- intolerant asthmatics (AIA). Mast cell activation markers and eosinophile also increase in BALF, suggesting that these cells are the sources of the cysteinyl leukotrienes. Considerable overlap is observed in mast cell activation markers in BALF among AIA and aspirin-tolerant asthmatics (ATA), suggesting that aspirin-intolerant asthma may be an extreme manifestation of some of the cellular, cytokine and eicosanoid inflammatory processes which characterize asthma. We hypothesize that the eosinophil, in concert with the mast cell, plays a central role in determining the development of the clinical response to COX inhibition in AIA and in the perpetuation of airway inflammation. The location and activation of eosinophile may be the key differentiating factors in determining whether the clinical and inflammatory response to cyclooxygenase inhibition occurs. In this study, AIA, ATA, and normal subjects undergo bronchoalveolar lavage and endobronchial biopsy, before and after endobronchial challenge with indomethacin. Products of the arachidonic acid cascade, including 15- hydroxyeicosatetraenoic acid (15- HETE), LTB4, and the cysteinyl leukotrienes are measured in BALF. Eosinophil chemoattractants, including IL-4, IL-5, RANTES, and eotaxin, and mast cell mediators are also measured in BALF. The modulatory effect of mast cell and T-cell mediators upon leukotrine production and migration activity of peripheral blood eosinophile is assessed. To date, we have demonstrated that COX inhibition causes release of 15-HETE in both AIA and ATA. This finding demonstrates that activation of the arachidonic acid cascade may not be unique to AIA, and that more overlap exists between AIA and ATA than has been previously realized. We anticipate that the increase in eosinophile after indomethacin will be related to increased amounts of at least one eosinophil chemoattractant in BAL cells, BALF, or endobronchial tissue. Furthermore, we expect that eosinophile from AIA will produce more leukotrienes than controls, and that they will demonstrate enhanced leukotriene production, as well as migration, in response to mast cell and T-lymphocyte mediators.