Characterization of a novel, papain‐inducible murine model of eosinophilic rhinosinusitis

Tharakan, Anuj; Dobzanski, Alex; London, Nyall R.; Khalil, Syed Muaz; Surya, Nitya; Lane, Andrew P.; Ramanathan, Murugappan

doi:10.1002/alr.22072

Cited by 14 publications

(14 citation statements)

References 42 publications

(57 reference statements)

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“…The cysteine protease inducible murine model of type 2 sinonasal inflammation provides an excellent experimental platform to dissect molecular mechanisms involved in CRS pathophysiology as previously described. 21 Mice were treated on days 0 to 2 and days 7 to 11, and sacrificed 24 hours after the final treatment.…”

Section: Papain-induced Model Of Rhinosinusitismentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Papain-induced Model Of Rhinosinusitismentioning

confidence: 99%

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

et al. 2020

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“… 10 , 11 Others have relied on murine and rabbit models of sinusitis to replicate the conditions of CRS and evaluate therapeutics on treatment arms and controls. Khalmuratova et al 12 were able to develop of a mouse model of CRSwNP using nasally injected HDM co-administered with staphylococcus aureus enterotoxin B. Tharaken et al 13 were also able to develop a murine model of eosinophilic rhinosinusitis following administration of intranasal papain with comparable Th2 cytokines and innate immune responses to CRS. While these models are essential for testing and understanding basic fundamental mechanisms, their clinical utility remains questionable.…”

Section: Aeroallergens – Pathogenesismentioning

confidence: 99%

Aeroallergens, air pollutants, and chronic rhinitis and rhinosinusitis

London

Lina

Ramanathan

2018

World j. otorhinolaryngol.-head neck surg.

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Chronic rhinitis and rhinosinusitis are among the most common conditions worldwide with significant morbidity and decreased quality of life. Although the pathogenesis of these conditions is multifactorial, there has been increasing evidence for the role of environmental factors such as aeroallergens and air pollutants as initiating or exacerbating factors. This review will outline the current literature focusing on the role of aeroallergens and air pollution in the pathogenesis of chronic sinonasal inflammatory conditions.

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“…Secondly, intranasal challenge with fungal conidia over 3 months represents a physiologically relevant exposure for the development of chronic respiratory inflammation. Other mouse models for CRS have been proposed, but fail to recapitulate the environmental exposures experienced by typical patients, e.g., by utilizing non-physiologic means to boost an immune response including intraperitoneal injections of fungi with or without adjuvant ( 6 ), use of purified proteases not typically inhaled from the environment ( 39 ), or short exposure times of less than 2 weeks ( 40 ). In contrast, our model of unified airway disease employs physiological exposure to inhaled conidia over an extended time period to more closely align with the development of chronic inflammation that is typical of CRS.…”

Section: Discussionmentioning

confidence: 99%

STAT6 Blockade Abrogates Aspergillus-Induced Eosinophilic Chronic Rhinosinusitis and Asthma, A Model of Unified Airway Disease

et al. 2022

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Unified airway disease, including concurrent asthma and chronic rhinosinusitis (CRS), is a common, but poorly understood disorder with no curative treatment options. To establish a murine model of chronic unified eosinophilic airway inflammation, mice were challenged with Aspergillus niger, and sinonasal mucosa and lung tissue were evaluated by immunohistochemistry, flow cytometry, and gene expression. Inhalation of A niger conidia resulted in a Th2-biased lung and sinus inflammation that typifies allergic asthma and CRS. Gene network and pathway analysis correlated with human disease with upregulation of not only the JAK-STAT and helper T-cell pathways, but also less expected pathways governing the spliceosome, osteoclast differentiation, and coagulation pathways. Utilizing a specific inhibitor and gene-deficient mice, we demonstrate that STAT6 is required for mycosis-induced sinus inflammation. These findings confirm the relevance of this new model and portend future studies that further extend our understanding of the immunopathologic basis of airway mycosis and unified airway disease.

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Characterization of a novel, papain‐inducible murine model of eosinophilic rhinosinusitis

Cited by 14 publications

References 42 publications

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

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

Aeroallergens, air pollutants, and chronic rhinitis and rhinosinusitis

STAT6 Blockade Abrogates Aspergillus-Induced Eosinophilic Chronic Rhinosinusitis and Asthma, A Model of Unified Airway Disease

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