MECHANISMS OF AIRWAY INFLAMMATION IN ASPIRIN INTOLERANT ASTHMA

阿司匹林不耐受哮喘是一种影响5-10%哮喘人群的临床综合征。环氧化酶（COX）抑制剂，如阿司匹林和吲哚美辛，刺激大量半胱氨酸白三烯释放到支气管肺泡灌洗液（BALF）在阿司匹林不耐受哮喘（AIA）。肥大细胞活化标记物和嗜酸性粒细胞也在BALF中增加，表明这些细胞是半胱氨酸白三烯的来源。在AIA中观察到BALF中肥大细胞激活标记物有相当大的普遍性，这可能是哮喘特征的一些细胞、细胞因子和类二十烷类炎症过程的极端表现。我们假设嗜酸性粒细胞与肥大细胞一起，在确定AIA对COX抑制的临床反应的发展和气道炎症的持续发展中起着核心作用。嗜酸性粒细胞的位置和激活可能是决定环加氧酶支气管肺泡灌洗和支气管活检以及支气管内吲哚美辛攻击前后临床和炎症反应的关键区分因素。花生四烯酸的产物，包括15-羟基二十碳四烯酸（15-HETE）。在BALF中测定LTB4和环丙基白三烯。嗜酸性粒细胞化学引诱剂，包括IL-4、IL-5、RANTES和eotaxin，以及肥大细胞介质也在BALF中检测。评估肥大细胞和t细胞介质对外周血嗜酸性粒细胞白三烯产生和迁移活性的调节作用。到目前为止，我们已经证明COX抑制会导致AIA和ATA中15-HETE的释放。这一发现表明，花生四烯酸级联的激活可能不是AIA独有的，AIA和ATA之间存在更多的重叠。我们预计，吲哚美辛后嗜酸性粒细胞的增加将与BAL细胞、BALF或支气管内组织中至少一种嗜酸性粒细胞化学引诱剂的增加有关。此外，我们预计来自AIA的嗜酸性粒细胞将比对照组产生更多的白三烯，并且它们将表现出增强的白三烯产生和迁移，以响应肥大细胞和t淋巴细胞介质。

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.