Ameisen J C, Capron A, Joseph M, Maclouf J, Vorng H, Pancré V, Fournier E, Wallaert B, Tonnel A B
Int Arch Allergy Appl Immunol. 1985;78(4):438-48. doi: 10.1159/000233927.
The pathogenesis of aspirin-sensitive asthma remains unknown. Using a new model of platelet activation, initially described as a response of platelets to IgE antibody-dependent stimuli, this study was designed to test the hypothesis of a possible involvement of platelets in aspirin-sensitive asthma. Washed platelets from 35 aspirin-sensitive asthmatics showed an abnormal in vitro response to cyclooxygenase inhibiting nonsteroidal anti-inflammatory drugs (NSAIDs)--aspirin, indomethacin or flurbiprofen--characterized by the generation of a cytocidal supernatant and (14 patients explored) a burst of chemiluminescence; these drugs had no similar effect on platelets from 31 controls (p less than 0.0001). It was shown that the abnormal platelet response to NSAIDs was not mediated by IgE. In contrast to platelets, aspirin-sensitive asthmatic leukocytes generated neither cytocidal factors nor chemiluminescence in the presence of NSAIDs. Sodium salicylate and salicylamide, which, though structurally similar to aspirin, do not inhibit cyclooxygenase and are well tolerated by aspirin-sensitive asthmatics, did not activate their platelets to release cytocidal factors. Moreover, preincubation of platelets with sodium salicylate, salicylamide or prostaglandin endoperoxide PGH2, highly prevented their abnormal response to NSAIDs (greater than 80%; p less than 0.0001). Since several lipoxygenase inhibitors (NDGA, esculetin), including inhibitors of both cyclooxygenase and lipoxygenase (ETYA, BW755c), did not activate patient platelets and prevented the subsequent abnormal response to NSAIDs, it is suggested that the abnormal platelet activation by NSAIDs is not only the consequence of an inhibition of cyclooxygenase, but also involves generation of lipoxygenase metabolites of arachidonate. Besides, platelets from 4 aspirin-sensitive asthmatics undergoing aspirin desensitization were found to have completely lost their abnormal responsiveness to NSAIDs. These findings represent the first identification in aspirin-intolerant asthmatics of a specific abnormal cellular response to drugs inducing asthmatic attacks and open new perspectives into the pathogenesis, prevention and diagnosis of this disease. They also provide support to the concept of a role for platelets in asthma.
阿司匹林敏感性哮喘的发病机制尚不清楚。本研究采用一种新的血小板激活模型（最初描述为血小板对IgE抗体依赖性刺激的反应），旨在验证血小板可能参与阿司匹林敏感性哮喘的假说。从35例阿司匹林敏感性哮喘患者采集的洗涤血小板，对环氧化酶抑制性非甾体抗炎药（NSAIDs）——阿司匹林、吲哚美辛或氟比洛芬——表现出异常的体外反应，其特征为产生具有细胞毒性的上清液以及（检测了14例患者）化学发光爆发；这些药物对31例对照者的血小板没有类似作用（p<0.0001）。结果表明，血小板对NSAIDs的异常反应不是由IgE介导的。与血小板不同，阿司匹林敏感性哮喘患者的白细胞在NSAIDs存在的情况下既不产生细胞毒性因子也不产生化学发光。水杨酸钠和水杨酰胺虽然在结构上与阿司匹林相似，但不抑制环氧化酶，且阿司匹林敏感性哮喘患者对其耐受性良好，它们不会激活患者的血小板释放细胞毒性因子。此外，血小板先用水杨酸钠、水杨酰胺或前列腺素内过氧化物PGH2预孵育，可高度预防其对NSAIDs的异常反应（>80%；p<0.0001）。由于几种脂氧合酶抑制剂（去甲二氢愈创木酸、七叶亭），包括环氧化酶和脂氧合酶双重抑制剂（ETYA、BW755c），不会激活患者的血小板，并能预防随后对NSAIDs的异常反应，提示NSAIDs引起的血小板异常激活不仅是环氧化酶抑制的结果，还涉及花生四烯酸脂氧合酶代谢产物的生成。此外，发现4例正在进行阿司匹林脱敏治疗的阿司匹林敏感性哮喘患者的血小板对NSAIDs的异常反应完全消失。这些发现首次在阿司匹林不耐受性哮喘患者中鉴定出对诱发哮喘发作的药物的特异性异常细胞反应，为该疾病的发病机制、预防和诊断开辟了新的前景。它们也为血小板在哮喘中起作用的概念提供了支持。
