基于氧代二十碳四烯酸的阿司匹林加重性呼吸系统疾病患者代谢组学内表型研究
2025/10/11
摘要
背景：阿司匹林加重性呼吸系统疾病（AERD）患者的花生四烯酸代谢特征在于促炎与抗炎类二十烷酸之间的失衡。本研究聚焦于15-LOX-1和5-LOX通路的终末代谢物。
目的：我们旨在基于血浆和尿液中15-氧代-二十碳四烯酸（15-oxo-ETE）和5-氧代-二十碳四烯酸的水平，结合其他脂氧合酶花生四烯酸代谢物及相关变量，识别可能的代谢组学聚类。
方法：对78例AERD患者和63例阿司匹林耐受性哮喘（ATA）患者进行层次聚类分析，共包含23个变量。这些变量涵盖人口统计学、临床、生化及治疗数据；鼻窦计算机断层扫描结果；以及通过高效液相色谱与串联质谱法测定的特定类二十烷酸的血浆和尿液水平。
结果：在每个研究组中均区分出两个聚类（内表型）。与ATA聚类相比，AERD聚类中的鼻窦CT Lund-Mackay评分和尿白三烯E4水平显著更高，而尿15-oxo-ETE水平显著更低。聚类1AERD（对比聚类2AERD）和聚类1ATA（对比聚类2ATA）中的患者年龄更大、体重指数更高、哮喘更严重且控制更差，同时血浆15-羟基二十碳四烯酸、15-oxo-ETE和5-羟基二十碳四烯酸水平更高。与ATA患者相比，AERD患者的鼻窦病变更严重，尿15-oxo-ETE和白三烯E4水平更高。
结论：在年龄较大、体重指数较高的AERD患者中，较高的血浆15-oxo-ETE水平和较低的尿液15-oxo-ETE水平与更严重的哮喘及更差的哮喘控制相关。
Metabolomic endophenotypes based on oxo-eicosatetraenoic acids in patients with aspirin-exacerbated respiratory disease
Piotr Szatkowski, Adam Stępień, Adam Ćmiel, Radosław Kacorzyk, Gabriela Trąd-Wójcik, Ewelina Gacek, Lucyna Mastalerz
Abstract
BACKGROUND:
Arachidonic acid metabolism in patients with aspirin-exacerbated respiratory disease (AERD) is characterized by an imbalance between proinflammatory and anti-inflammatory eicosanoids. In this study, we focused on end metabolites of the 15-LOX-1 and 5-LOX pathways.
OBJECTIVE:
We sought to identify possible metabolomic clusters based on plasma and urinary levels of 15-oxo-eicosatetraenoic acid (15-oxo-ETE) and 5-oxo-eicosatetraenoic acid in combination with other lipoxygenase arachidonic acid metabolites and variables.
METHODS:
Hierarchical cluster analysis was performed in 78 patients with AERD and 63 patients with aspirin-tolerant asthma (ATA), both with 23 variables. These variables included demographic, clinical, biochemical, and treatment data; sinus computed tomography findings; and plasma and urinary levels of selected eicosanoids measured by high-performance liquid chromatography and tandem mass spectrometry.
RESULTS:
Two clusters (endophenotypes) were distinguished in each study group. The Lund-Mackay score on paranasal sinus computed tomography and urinary leukotriene E4 levels were significantly higher, whereas urinary 15-oxo-ETE levels were significantly lower, in AERD clusters compared with ATA clusters. Patients in cluster 1AERD (vs cluster 2AERD) and cluster 1ATA (vs cluster 2ATA) were older and had higher body mass index, more severe asthma, and worse asthma control, as well as higher levels of plasma 15-hydroxyeicosatetraenoic acid, 15-oxo-ETE, and 5-hydroxyeicosatetraenoic acid. Patients with AERD had more advanced changes in the sinuses and higher urinary levels of 15-oxo-ETE and leukotriene E4 than patients with ATA.
CONCLUSION:
Higher plasma and lower urinary levels of 15-oxo-ETE are associated with more severe asthma and worse asthma control in patients with AERD with older age and higher body mass index.
背景：阿司匹林加重性呼吸系统疾病（AERD）患者的花生四烯酸代谢特征在于促炎与抗炎类二十烷酸之间的失衡。本研究聚焦于15-LOX-1和5-LOX通路的终末代谢物。
目的：我们旨在基于血浆和尿液中15-氧代-二十碳四烯酸（15-oxo-ETE）和5-氧代-二十碳四烯酸的水平，结合其他脂氧合酶花生四烯酸代谢物及相关变量，识别可能的代谢组学聚类。
方法：对78例AERD患者和63例阿司匹林耐受性哮喘（ATA）患者进行层次聚类分析，共包含23个变量。这些变量涵盖人口统计学、临床、生化及治疗数据；鼻窦计算机断层扫描结果；以及通过高效液相色谱与串联质谱法测定的特定类二十烷酸的血浆和尿液水平。
结果：在每个研究组中均区分出两个聚类（内表型）。与ATA聚类相比，AERD聚类中的鼻窦CT Lund-Mackay评分和尿白三烯E4水平显著更高，而尿15-oxo-ETE水平显著更低。聚类1AERD（对比聚类2AERD）和聚类1ATA（对比聚类2ATA）中的患者年龄更大、体重指数更高、哮喘更严重且控制更差，同时血浆15-羟基二十碳四烯酸、15-oxo-ETE和5-羟基二十碳四烯酸水平更高。与ATA患者相比，AERD患者的鼻窦病变更严重，尿15-oxo-ETE和白三烯E4水平更高。
结论：在年龄较大、体重指数较高的AERD患者中，较高的血浆15-oxo-ETE水平和较低的尿液15-oxo-ETE水平与更严重的哮喘及更差的哮喘控制相关。
（中日友好医院呼吸与危重症医学科 李春晓 摘译 林江涛 审校）
（J Allergy Clin Immunol. 2025 Sep;156(3):616-626.DOI: 10.1016/j.jaci.2025.04.036.）
Metabolomic endophenotypes based on oxo-eicosatetraenoic acids in patients with aspirin-exacerbated respiratory disease
Piotr Szatkowski, Adam Stępień, Adam Ćmiel, Radosław Kacorzyk, Gabriela Trąd-Wójcik, Ewelina Gacek, Lucyna Mastalerz
Abstract
BACKGROUND:
Arachidonic acid metabolism in patients with aspirin-exacerbated respiratory disease (AERD) is characterized by an imbalance between proinflammatory and anti-inflammatory eicosanoids. In this study, we focused on end metabolites of the 15-LOX-1 and 5-LOX pathways.
OBJECTIVE:
We sought to identify possible metabolomic clusters based on plasma and urinary levels of 15-oxo-eicosatetraenoic acid (15-oxo-ETE) and 5-oxo-eicosatetraenoic acid in combination with other lipoxygenase arachidonic acid metabolites and variables.
METHODS:
Hierarchical cluster analysis was performed in 78 patients with AERD and 63 patients with aspirin-tolerant asthma (ATA), both with 23 variables. These variables included demographic, clinical, biochemical, and treatment data; sinus computed tomography findings; and plasma and urinary levels of selected eicosanoids measured by high-performance liquid chromatography and tandem mass spectrometry.
RESULTS:
Two clusters (endophenotypes) were distinguished in each study group. The Lund-Mackay score on paranasal sinus computed tomography and urinary leukotriene E4 levels were significantly higher, whereas urinary 15-oxo-ETE levels were significantly lower, in AERD clusters compared with ATA clusters. Patients in cluster 1AERD (vs cluster 2AERD) and cluster 1ATA (vs cluster 2ATA) were older and had higher body mass index, more severe asthma, and worse asthma control, as well as higher levels of plasma 15-hydroxyeicosatetraenoic acid, 15-oxo-ETE, and 5-hydroxyeicosatetraenoic acid. Patients with AERD had more advanced changes in the sinuses and higher urinary levels of 15-oxo-ETE and leukotriene E4 than patients with ATA.
CONCLUSION:
Higher plasma and lower urinary levels of 15-oxo-ETE are associated with more severe asthma and worse asthma control in patients with AERD with older age and higher body mass index.
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