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 eukotrienes into bronchoalveolar lavage fluid (BALF) in aspirin-intolerant asthmatics (AIA). Mast cell activation markers and eosinophils also increase in BALF, sugggesting that these cells are the sources of the cysteinyl leukotrienes. Considerable overalp is observed in mast cell activation markers in BALF among AIA and 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 inhibitation in AIA and in the perpetuation of airway inflammation. The location and activation of eosinophils may be the key differentiating factors in determining whether the clinical and inflammatory response to cyclooxygenase bronchoalveolar lavage and endobronchial biopsy, before and after endobronchial challenge with indomethacin. Products of the arachidonic acid casecade, including 15-hydroxyeicosatetraenoic acid (15-HETE). LTB4, and the cycteinyl leukotrienes are measured in BALF. Eosinophil chemoattractants, cinlduing IL-4, IL-5, RANTES, and eotaxin, and mast cell mediatros are also measured in BALF. The modulatory effect of mast cell and T-cell mediatros upon leukotriene production and migration activity of peripheral blood eosinophils is asssessed. To date, we have demonstrated that COX inhibitation causes release of 15-HETE in both AIA and ATA. This fidning 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 eosinophils 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 eosinophils 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-lymphycyte mediatros.