Activation of the 15-lipoxygenase pathway in aspirin-exacerbated respiratory disease - 04/02/21
, Anna G. Staudacher, MS a, ∗, Kathryn E. Hulse, PhD a, Roderick G. Carter, BS a, Deborah R. Winter, PhD c, Hiam Abdala-Valencia, PhD d, Atsushi Kato, PhD a, Lydia Suh, BS a, James E. Norton, MS a, Julia H. Huang, MS b, Anju T. Peters, MD a, b, Leslie C. Grammer, MD a, Caroline P.E. Price, BA b, David B. Conley, MD b, Stephanie Shintani-Smith, MD b, Bruce K. Tan, MD, MS b, Kevin C. Welch, MD b, Robert C. Kern, MD b, Robert P. Schleimer, PhD a, bAbstract |
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.
Le texte complet de cet article est disponible en PDF.Key words : Chronic sinusitis, nasal polyps, CRSwNP, AERD, aspirin-exacerbated respiratory disease, 15-lipoxygenase, ALOX15, 15-oxo-eicosatetraenoic acid, hydroxyprostaglandin dehydrogenase
Abbreviations used : AA, AERD, COX-1, CRS, CRSwNP, CRSsNP, HPLC-MS/MS, IT, 15-HETE, 15-HETE–PE, HPGD, 5-LO, 15-LO, LTE4, NP, 15-Oxo-ETE, qRT-PCR, scRNA-seq, UT
Plan
| Supported in part by the grants from the National Institutes of Health (grants KL2 TR001424, K23 AI141694, R01 AI104733, U19 AI106683, and P01 145818), grants from the Parker B. Francis Fellowship Foundation, the HOPE APFED/AAAAI Pilot Grant Award, and the Ernest S. Bazley Foundation. |
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| Disclosure of potential conflict of interest: W. Stevens served on an advisory board for GlaxoSmithKline. A. Kato reports personal fees from Astellas Pharmaceuticals. B. Tan reports personal fees from Sanofi Regeneron/Genzyme, and OptiNose. A. Peters reports personal fees from Sanofi Regeneron and personal fees and grants from AstraZeneca. L. Grammer reports personal fees from Astellas Pharmaceuticals. R. Kern reports personal fees from Sanofi, Novartis, Lyra Pharmaceutical, and Neurent. R. Schleimer reports personal fees from Intersect ENT, Merck, GlaxoSmithKline, Sanofi, AstraZeneca/Medimmune, Genentech, Actobio Therapeutics, Lyra Therapeutics, Astellas Pharma, Inc, and Otsuka Inc; in addition, R. Schleimer has Siglec-8– and Siglec-8 ligand–related patents licensed to Allakos Inc. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 147 - N° 2
P. 600-612 - février 2021 Retour au numéro
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