Disruption of Sinonasal Epithelial Nrf2 Enhances Susceptibility to Rhinosinusitis in a Mouse Model

Abstract

Objectives/Hypothesis: Oxidative stress has been postulated to play an important role in chronic rhinosinusitis. Nrf2 is a transcription factor that is involved in the regulation of multiple antioxidant genes, and its function has been previously shown to be important in sinonasal inflammation. Although the sinonasal implications of whole body Nrf2 −/− has been reported, the function of sinonasal epithelial expression of Nrf2 has not been studied. The primary aim of this study was to generate a mouse model that is genetically deficient in epithelial-specific Nrf2 and to understand its role in regulating sinonasal inflammation. Study Design: Basic science. Methods: An epithelial-specific Nrf2 knockout mouse was generated by crossing Krt5-cre(K5) with Nrf2 flox/flox. A papaininduced model of rhinosinusitis was performed in the resulting K5 Nrf2 −/− mouse. Immunohistochemistry was performed to quantify goblet cell hyperplasia. Mucosal cellular infiltrates were quantified using flow cytometry, and tissue cytokines were measured using an enzyme-linked immunosorbent assay. Lastly, the cellular source of type 2 cytokines was determined using intracellular cytokine staining. Results: Papain-sensitized mice lacking epithelial-specific Nrf2 demonstrate increased goblet cell hyperplasia, significant tissue eosinophilia, and statistically significant increase in mucosal IL-13 when compared to Nrf2 wild-type mice. Lastly, mucosal T cells were identified as the cellular source of IL-13. Conclusions: We demonstrate enhanced severity of eosinophilic sinonasal inflammation from disruption of the epithelialspecific Nrf2 pathway. The responsiveness of Nrf2-directed antioxidant pathways may act as a major determinant of susceptibility to eosinophilic inflammation and may have potential as a therapeutic target for chronic rhinosinusitis.

Downregulation of TET2 Contributes to Nasal Polypogenesis Through Hypoxia-Inducible Factor 1α-Mediated Epithelial-to-Mesenchymal Transition

“…To date, there is limited evidence regarding the role of Nrf2 in CRS. Studies using epithelial-specific Nrf2 knockout mice have shown that these mice exhibit goblet cell proliferation and significant eosinophilic infiltration in the nasal epithelium following a papain-induced model of rhinosinusitis, compared to wild-type mice [ 41 ]. Additionally, Nrf2 activation has been shown to recover cigarette smoke-induced epithelial barrier dysfunction in the nasal mucosa [ 42 ].…”

Particulate matter exposure is associated with increased inflammatory cytokines and eosinophils in chronic rhinosinusitis

“…22 Other studies utilizing a rabbit model of CRS showed alterations and disorganization of ciliary structures, goblet cell hyperplasia, and collagen deposition using electron microscopy, further implicating the role of PM 2.5 in sinonasal inflammation and tissue remodeling. 23,24 A small pilot study of six patients with nasal polyps or allergic rhinitis in Beijing also noted statistically significant elevations in nasal mucus IL-1β, IL-6, IL-8, and IL-5 when measured on high PM 2.5 days compared to low PM 2.5 days, suggesting a dose-dependent response of the nasal mucosa to PM 2.5 exposure. 25 No study to date, however, has assessed the impact of chronic PM 2.5 exposure on the nasal mucosa in CRS.…”

Oxidative Stress and Air Pollution: Its Impact on Chronic Respiratory Diseases

“…For example, Nrf2 was necessary for an antioxidant pathway in a mouse model of rhinosinusitis. Knockout mice showed enhanced severity of eosinophilic sinonasal inflammation from disruption of the epithelial-specific Nrf2 pathway [16] and enhanced susceptibility to eosinophilic sinonasal inflammation [17]. This transcription factor has also been related to the stability of the sinonasal epithelial cell barrier function [18].…”