A Novel Role for 15-Lipoxygenase Metabolites in Aspirin Exacerbated Respiratory Disease

Abstract

Aspirin Exacerbated Respiratory Disease (AERD) is defined by the triad of asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), and an intolerance to cyclooxygenase-1 inhibitors. AERD patients tend to have more severe respiratory disease than aspirin-tolerant patients with CRSwNP. The underlying mechanisms contributing to enhanced disease in AERD are not understood, but a dysregulation in arachidonic acid metabolism is important. We investigated the 15-lipoxygenase (15-LO) pathway in AERD pathogenesis. We examined expression levels of genes important for the synthesis and function of arachidonic acid metabolites in AERD and CRSwNP NP by single-cell RNA sequencing using the 10X Genomics platform and by traditional RT-PCR. Lipid mediators were measured in sinonasal tissue by mass spectrometry. Immunofluorescence was used to examine localization of specific enzymes within NP. ALOX15 expression was significantly elevated in AERD compared to CRSwNP NP (p<0.05) and control tissue (p<0.001) and was predominantly expressed in epithelial cells. ALOX15expression significantly correlated with radiographic sinus disease severity (r=0.56, p<0.001) and was associated with comorbid asthma in CRSwNP. 15-oxo-ETE, a downstream product of 15-LO, was significantly elevated in CRSwNP (27.93 pg/mg tissue) and AERD (61.03 pg/mg tissue) NP compared to control (7.17 pg/mg tissue, p<0.001). Hydroxyprostaglandin dehydrogenase, an enzyme required for 15-oxo-ETE synthesis, was predominantly expressed in mast cells and, by immunofluorescence, 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 as well as to the enhanced sinonasal disease severity observed in AERD.