Activation of the 15-lipoxygenase pathway in aspirin-exacerbated respiratory disease

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:147

Article

Stevens, Whitney W.^1,2  Staudacher, Anna G.¹  Hulse, Kathryn E.¹  Carter, Roderick G.¹  Winter, Deborah R.³  Abdala-Valencia, Hiam⁴  Kato, Atsushi¹  Suh, Lydia¹  Norton, James E.¹  Huang, Julia H.²  Peters, Anju T.^1,2  Grammer, Leslie C.¹  Price, Caroline P. E.²  Conley, David B.²  Shintani-Smith, Stephanie²  Tan, Bruce K.²  Welch, Kevin C.²  Kern, Robert C.²  Schleimer, Robert P.^1,2 

[1] Northwestern Univ, Feinberg Sch Med, Dept Med, Div Allergy & Immunol, Chicago, IL USA

[2] Northwestern Univ, Feinberg Sch Med, Dept Otolaryngol, Chicago, IL USA

[3] Northwestern Univ, Feinberg Sch Med, Div Rheumatol, Dept Med, Chicago, IL USA

[4] Northwestern Univ, Feinberg Sch Med, Div Pulm & Crit Care Med, Dept Med, Chicago, IL USA

关键词: Chronic sinusitis;    nasal polyps;    CRSwNP;    AERD;    aspirin-exacerbated respiratory disease;    15-lipoxygenase;    ALOX15;    15-oxo-eicosatetraenoic acid;    hydroxyprostaglandin dehydrogenase;   

DOI  :  10.1016/j.jaci.2020.04.031

来源: Elsevier

【 摘 要 】

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 (103 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.

【 授权许可】

Free