MECHANISMS OF AIRWAY INFLAMMATION IN ASPIRIN INTOLERANT ASTHMA

阿司匹林不耐受哮喘是一种临床综合征，影响5%-10%的 哮喘患者。环氧合酶(COX)抑制剂，如阿司匹林和 消炎痛，刺激大量半胱氨酸基的释放 阿司匹林中白三烯进入支气管肺泡灌洗液(BALF)- 不耐受哮喘患者(AIA)。肥大细胞活化标志物与嗜酸性粒细胞 在BALF中也增加，这表明这些细胞是 半胱氨基白三烯。在肥大细胞中观察到相当大的重叠 AIA和阿司匹林耐受性哮喘患者BALF中的活化标志物 (ATA)，表明阿司匹林不耐受哮喘可能是一种极端 某些细胞、细胞因子和二十烷类化合物的表现 以哮喘为特征的炎症过程。我们假设 嗜酸性粒细胞与肥大细胞协同作用在 确定COX抑制的临床反应的发展 AIA和持续的呼吸道炎症中。位置和 嗜酸性粒细胞的激活可能是该病的关键区别因素 确定临床和炎症反应是否 环氧合酶受到抑制。在本研究中，AIA、ATA和NORMAL 受试者在接受支气管肺泡灌洗和支气管镜活检前 在支气管内用消炎痛激发后。该公司的产品 花生四烯酸级联，包括15-羟基二十碳四烯酸(15- HETE)、LTB4和半胱氨基白三烯在BALF中被测量。 嗜酸性粒细胞趋化因子，包括IL-4、IL-5、RANTES和嗜酸性粒细胞趋化因子， 在BALF中也可检测到肥大细胞介质。调制效应 肥大细胞和T细胞介质对白三氨酸产生和迁移的影响 检测外周血嗜酸性粒细胞活性。到目前为止，我们有 证明COX抑制导致AIA和AIA中15-HETE的释放 阿塔。这一发现表明，花生四烯酸的激活 级联可能不是AIA独有，且AIA之间存在更多重叠 和ATA比之前实现的要好。我们预计这一增长 在嗜酸性粒细胞中消炎痛后将与量增加有关 至少一种嗜酸性粒细胞趋化剂在BAL细胞、BALF或 支气管内膜组织。此外，我们预计来自友邦保险的嗜酸性粒细胞 会比对照组产生更多的白三烯，而且他们会 展示了白三烯产量的增加，以及在 对肥大细胞和T淋巴细胞介体的反应。

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.