Activation of the 15-Lipoxygenase Pathway in Aspirin Exacerbated Respiratory Disease

Abstract Background 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. Objective To utilize an unbiased approach investigating arachidonic acid metabolic pathways in AERD. Methods 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. Results The gene encoding for 15-LO, ALOX15, was significantly elevated in NP of AERD compared to CRSwNP (p 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.