Activation of the 15-lipoxygenase pathway in aspirin-exacerbated respiratory disease.
Activation of the 15-lipoxygenase pathway in aspirin-exacerbated respiratory disease.
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阿司匹林加重的呼吸道疾病中15-脂氧合酶途径的激活。
DOI：
10.1016/j.jaci.2020.04.031
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Schleimer RP
中科院分区：
文献类型：
--
作者：
Stevens WW;Staudacher AG;Hulse KE;Carter RG;Winter DR;Abdala-Valencia H;Kato A;Suh L;Norton JE;Huang JH;Peters AT;Grammer LC;Price CPE;Conley DB;Shintani-Smith S;Tan BK;Welch KC;Kern RC;Schleimer RP
阿司匹林加重呼吸系统疾病（AERD）的特点是哮喘、慢性鼻窦炎伴鼻息肉（CRSwNP）和对抑制环氧化酶-1的药物不耐受。与阿司匹林耐受的CRSwNP患者相比，AERD患者有更严重的上、下呼吸道疾病。花生四烯酸代谢失调被认为是导致AERD鼻窦炎症增强的原因。利用无偏倚的方法研究花生四烯酸在AERD中的代谢途径。使用单细胞RNA测序（10X Genomics）比较AERD和CRSwNP患者NP细胞的转录谱，并绘制所鉴定细胞类型中选定基因表达的差异。结果经传统RT-PCR证实。用质谱法测定鼻腔组织中的脂质介质。免疫荧光法测定NP内各种蛋白的定位。与CRSwNP相比，AERD患者NP中编码15-LO的基因ALOX15显著升高（p<0.05）或对照组（p<0.001）。ALOX15主要在上皮细胞中表达。表达水平与影像学上鼻窦疾病严重程度显著相关（r=0.56, p<0.001），并与哮喘相关。15-LO的下游产物15-oxo-ETE在CRSwNP （27.93pg/mg组织）和AERD （61.03pg/mg组织）NP中显著高于对照组（7.17pg/mg组织，p<0.001）。羟前列腺素脱氢酶是合成15-oxo-ETE所需的酶，主要在肥大细胞中表达，并定位于AERD NP的15-LO+上皮附近。上皮细胞和肥大细胞的相互作用导致15-oxo-ETE的合成，可能通过15-LO途径导致花生四烯酸代谢失调，并在AERD中观察到鼻窦疾病严重程度的增强。上皮细胞和肥大细胞的相互作用导致15-氧-二十碳四烯酸的合成，可能通过15-脂氧合酶途径导致花生四烯酸代谢失调，并导致AERD中鼻窦疾病严重程度的增加。
Aspirin Exacerbated Respiratory Disease (AERD) is characterized by asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), and an intolerance to medications that inhibit cyclooxygenase-1. AERD patients have more severe upper and lower respiratory tract disease compared to aspirin-tolerant CRSwNP patients. A dysregulation in arachidonic acid metabolism is thought to contribute to the enhanced sinonasal inflammation in AERD. To utilize an unbiased approach investigating arachidonic acid metabolic pathways in AERD. Single-cell RNA sequencing (10X Genomics) was utilized to compare the transcriptional profile of NP cells from AERD and CRSwNP patients and map differences in the expression of select genes among identified cell types. Findings were confirmed by traditional RT-PCR. Lipid mediators were measured in sinonasal tissue by mass spectrometry. Localization of various proteins within NP was assessed by immunofluorescence. The gene encoding for 15-LO, ALOX15, was significantly elevated in NP of AERD compared to CRSwNP (p<0.05) or control (p<0.001). ALOX15 was predominantly expressed by epithelial cells. Expression levels significantly correlated with radiographic sinus disease severity (r=0.56, p<0.001) and were associated with asthma. 15-oxo-ETE, a downstream product of 15-LO, was significantly elevated in CRSwNP (27.93pg/mg tissue) and AERD (61.03pg/mg tissue) NP compared to control (7.17pg/mg tissue, p<0.001). Hydroxyprostaglandin dehydrogenase, an enzyme required for 15-oxo-ETE synthesis, was predominantly expressed in mast cells and localized near 15-LO+ epithelium in AERD NP. 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. Epithelial and mast cell interactions, leading to the synthesis of 15-oxo-eicosatetraenoic acid, may contribute to the dysregulation of arachidonic acid metabolism via the 15-Lipoxygenase pathway and to the enhanced sinonasal disease severity observed in AERD.
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影响因子：
30.8
作者：
Kristjansson, Ragnar P.;Benonisdottir, Stefania;Stefansson, Kari
通讯作者：
Stefansson, Kari
影响因子：
14.2
作者：
Pérez-Novo, CA;Watelet, JB;Bachert, C
通讯作者：
Bachert, C
影响因子：
14.2
作者：
Hajek, Amanda R.;Lindley, Alexa R.;Favoreto, Silvio, Jr.;Carter, Roderick;Schleimer, Robert P.;Kuperman, Douglas A.
通讯作者：
Kuperman, Douglas A.
影响因子：
6.1
作者：
Chu, H. W.;Balzar, S.;Wenzel, S. E.
通讯作者：
Wenzel, S. E.
影响因子：
3.9
作者：
KUMLIN, M;HAMBERG, M;DAHLEN, SE
通讯作者：
DAHLEN, SE