Picado César, Machado-Carvalho Liliana, Roca-Ferrer Jordi
Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, 08907 Barcelona, Spain.
Centro de Investigaciones en Red de Enfermedades Respiratorias (CIBERES), 28029 Madrid, Spain.
J Clin Med. 2024 Dec 5;13(23):7416. doi: 10.3390/jcm13237416.
In patients with aspirin-exacerbated respiratory disease (AERD), there is disparate regulation of prostaglandin E2 (PGE) and prostaglandin D (PGD). Both prostanoids are synthesised by cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2). However, while the basal synthesis of PGE tends to decrease, that of PGD increases in patients with AERD. Furthermore, both behave differently in response to the inhibitory action of NSAIDs on COX-1: PGE levels decrease while PGD increases. Increased PGD release correlates with nasal, bronchial, and extra-pulmonary symptoms caused by aspirin in AERD. The proposed hypothesis establishes that the answer to this paradoxical dissociation can be found in the airway epithelium. This is based on the observation that reduced COX-2 mRNA and/or protein expression is associated with reduced PGE synthesis in cultured fibroblast and epithelial cells from AERD compared to patients with asthma who are aspirin-tolerant and healthy subjects. The low production of PGE by the airway epithelium in AERD results in an excessive release of alarmins (TSLP, IL-33), which in turn contributes to activating group 2 innate lymphoid cells (ILC2s) and PGD synthesis by mast cells and eosinophils. Aspirin, by further increasing the diminished PGE regulation capacity in AERD, leads to respiratory reactions associated with the surge in PGD from mast cells and eosinophils. In summary, the downregulation of COX-2 and the subsequent low production of PGE by airway cells account for the apparently paradoxical increased production of PGD by mast cells and eosinophils at the baseline and after aspirin provocation in patients with AERD. A better understanding of the role of the airway epithelium would contribute to elucidating the mechanism of AERD.
在阿司匹林加重性呼吸系统疾病（AERD）患者中，前列腺素E2（PGE）和前列腺素D（PGD）的调节存在差异。这两种前列腺素均由环氧化酶1（COX-1）和环氧化酶2（COX-2）合成。然而，在AERD患者中，虽然PGE的基础合成趋于减少，但PGD的基础合成却增加。此外，二者对非甾体抗炎药（NSAIDs）对COX-1的抑制作用表现不同：PGE水平降低而PGD水平升高。PGD释放增加与AERD中阿司匹林引起的鼻部、支气管和肺外症状相关。提出的假说认为，这种矛盾性解离的答案可以在气道上皮中找到。这是基于以下观察结果：与阿司匹林耐受的哮喘患者和健康受试者相比，来自AERD患者的培养成纤维细胞和上皮细胞中，COX-2 mRNA和/或蛋白表达降低与PGE合成减少有关。AERD患者气道上皮中PGE产生不足导致警报素（TSLP、IL-33）过度释放，进而促使2型固有淋巴细胞（ILC2s）活化以及肥大细胞和嗜酸性粒细胞合成PGD。阿司匹林通过进一步增加AERD中已减弱的PGE调节能力，导致与肥大细胞和嗜酸性粒细胞中PGD激增相关的呼吸反应。总之，气道细胞中COX-2的下调以及随后PGE产生不足，解释了AERD患者在基线时以及阿司匹林激发后肥大细胞和嗜酸性粒细胞中PGD产生明显矛盾性增加的现象。更好地理解气道上皮的作用将有助于阐明AERD的机制。
