Background

Aspirin-exacerbated respiratory disease (AERD) is characterized by asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), and an intolerance of medications that inhibit cyclooxygenase-1. Patients with AERD have more severe upper and lower respiratory tract disease than do aspirin-tolerant patients with CRSwNP. A dysregulation in arachidonic acid metabolism is thought to contribute to the enhanced sinonasal inflammation in AERD.

Objective

Our aim was to utilize an unbiased approach investigating arachidonic acid metabolic pathways in AERD.

Methods

Single-cell RNA sequencing (10× Genomics, Pleasanton, Calif) was utilized to compare the transcriptional profile of nasal polyp (NP) cells from patients with AERD and patients with CRSwNP and map differences in the expression of select genes among identified cell types. Findings were confirmed by traditional real-time PCR. Lipid mediators in sinonasal tissue were measured by mass spectrometry. Localization of various proteins within NPs was assessed by immunofluorescence.

Results

The gene encoding for 15-lipooxygenase (15-LO), ALOX15, was significantly elevated in NPs of patients with AERD compared to NPs of patients with CRSwNP (P < .05) or controls (P < .001). ALOX15 was predominantly expressed by epithelial cells. Expression levels significantly correlated with radiographic sinus disease severity (r = 0.56; P < .001) and were associated with asthma. The level of 15-oxo-eicosatetraenoic acid (15-Oxo-ETE), a downstream product of 15-LO, was significantly elevated in NPs from patients with CRSwNP (27.93 pg/mg of tissue) and NPs from patients with AERD (61.03 pg/mg of tissue) compared to inferior turbinate tissue from controls (7.17 pg/mg of tissue [P < .001]). Hydroxyprostaglandin dehydrogenase, an enzyme required for 15-Oxo-ETE synthesis, was predominantly expressed in mast cells and localized near 15-LO⁺ epithelium in NPs from patients with AERD.

Conclusions

Epithelial and mast cell interactions, leading to the synthesis of 15-Oxo-ETE, may contribute to the dysregulation of arachidonic acid metabolism via the 15-LO pathway and to the enhanced sinonasal disease severity observed in AERD.

中文翻译：

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阿司匹林加重呼吸系统疾病中 15-脂氧合酶途径的激活

背景

阿司匹林加重呼吸系统疾病 (AERD) 的特征是哮喘、慢性鼻窦炎伴鼻息肉 (CRSwNP) 以及对抑制 cyclooxygenase-1 的药物不耐受。与阿司匹林耐受的 CRSwNP 患者相比，AERD 患者的上呼吸道和下呼吸道疾病更为严重。花生四烯酸代谢的失调被认为是导致 AERD 中鼻窦炎症增强的原因。

客观的

我们的目标是利用一种公正的方法来研究 AERD 中的花生四烯酸代谢途径。

方法

单细胞 RNA 测序（10× Genomics，Pleasanton，Calif）用于比较来自 AERD 患者和 CRSwNP 患者的鼻息肉 (NP) 细胞的转录谱，并绘制选定基因在已识别细胞类型中表达的差异。研究结果通过传统的实时 PCR 得到证实。通过质谱法测量鼻窦组织中的脂质介质。通过免疫荧光评估 NP 内各种蛋白质的定位。

结果

与 CRSwNP ( P  < .05) 或对照组 ( P  < .001)患者的 NP 相比，AERD 患者的 NP 中编码 15-脂氧合酶 (15-LO) 的基因ALOX15显着升高。ALOX15主要由上皮细胞表达。表达水平与放射学鼻窦疾病严重程度显着相关（r  = 0.56；P  < .001）并与哮喘相关。15-LO 的下游产物 15-氧代-二十碳四烯酸 (15-Oxo-ETE) 的水平在 CRSwNP（27.93 pg/mg 组织）患者的 NP 和来自 AERD 患者的 NP（61.03 pg/mg 组织）与对照组的下鼻甲组织（7.17 pg/mg 组织 [P  < .001]）。羟基前列腺素脱氢酶是 15-Oxo-ETE 合成所需的一种酶，主要在肥大细胞中表达，并且位于来自 AERD 患者的 NPs 中的15-LO ^{+上皮附近。}

结论

导致 15-Oxo-ETE 合成的上皮细胞和肥大细胞相互作用可能导致通过 15-LO 途径的花生四烯酸代谢失调和在 AERD 中观察到的鼻窦疾病严重程度增加。