Abstract
Background: The pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP) and mechanisms underlying different responses to systemic glucocorticoids (GC) remain unclear. The major aim of this study was to explore the transcriptomic and oxidative lipidomic signatures and the effects of GC in patients with different clinical responses. Methods: Nasal polyp biopsies were obtained before and after 14-day oral GC treatment from 16 patients with CRSwNP, and normal nasal mucosa specimens were collected from 12 control subjects. RNA sequencing and oxidative lipidomics were performed, and differential gene expression analysis was conducted in the Responder and Non-responder groups at baseline and after treatment. Results: In the Responder group, GC significantly improved clinical symptoms and reduced tissue eosinophil infiltration. Meanwhile, GC led to a pronounced transcriptomic reversion with robust suppression of inflammatory responses and abnormal metabolism of extracellular matrix, as well as restoration of cilia function. However, non-responders were mainly characterized by epithelial hyperplasia and keratinization, with much less transcriptomic improvement after GC treatment. Higher expression of type 2 inflammatory molecules (CCL13, IGHE, CCL18, CCL23, CCR3, and CLC) with lower levels of LACRT, PPDPFL, DES, C6, MUC5B, and SCGB3A1 were related to a stronger clinical response to GC. Besides decreased prostaglandins and increased leukotrienes, increased dysregulation in other oxylipid mediators derived from polyunsaturated fatty acids was determined in nasal polyps, which was ameliorated by GC treatment. Conclusion: Systemic GC exert anti-inflammatory effects, improve tissue remodeling, restore cilia function, and ameliorate dysregulation of oxylipid mediator pathway in CRSwNP. GC-responders exhibited different transcriptomic signatures from non-responders.
Highlights
Chronic rhinosinusitis with nasal polyp (CRSwNP) is a common chronic inflammatory disorder leading to nasal obstruction, rhinorrhea, loss of smell, and facial pain for over 12 weeks (Fokkens et al, 2020)
Sixteen patients with CRSwNP were divided into two groups based on the change of Nasal Polyp Size Score (NPSS): Responder (R, n 11) and Nonresponder groups (N, n 5)
We identified 3,533 Differentially expressed genes (DEGs) (Supplementary Figure S5A, 1487 upregulated and 2046 downregulated) in all CRSwNP subjects compared with controls
Summary
Chronic rhinosinusitis with nasal polyp (CRSwNP) is a common chronic inflammatory disorder leading to nasal obstruction, rhinorrhea, loss of smell, and facial pain for over 12 weeks (Fokkens et al, 2020). Prostaglandin (PG) and leukotrienes (LT) are the most widely investigated eicosanoids in allergic diseases and CRSwNP (Peebles, 2019; Miyata et al, 2020a). Dysregulation in the arachidonic acid (AA) metabolism pathway, which is characterized by upregulation of the proinflammatory leukotriene pathway and downregulation of the antiinflammatory prostaglandin E2 (PGE2) pathway, has been detected in nasal polyps, especially in eosinophilic cases and patients with aspirin-exacerbated respiratory diseases (AERD) (Pérez-Novo et al, 2005; Wu et al, 2016; Kowalski et al, 2019). Multi-omics analysis has revealed that LTD4 production in nasal polyp-derived eosinophils is selectively enhanced (Miyata et al, 2019). The pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP) and mechanisms underlying different responses to systemic glucocorticoids (GC) remain unclear. The major aim of this study was to explore the transcriptomic and oxidative lipidomic signatures and the effects of GC in patients with different clinical responses
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