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Multiple airborne allergen-induced eosinophilic chronic rhinosinusitis murine model

  • Rhinology
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Abstract

Purpose

Several murine models have been established to mimic human eosinophilic chronic rhinosinusitis (ECRS). However, in most of these models, ECRS was induced using ovalbumin, which does not cause sinusitis in humans. Thus, we aimed to develop a more clinically relevant murine model of ECRS using multiple airborne allergens. We also investigated the effects of exposure duration of the allergens on ECRS development.

Methods

C57BL/6 mice were intranasally administered multiple airborne allergens (house dust mite, Aspergillus fumigatus, Alternaria alternata, and protease from Staphylococcus aureus) three times weekly for 4, 8, 12, and 16 consecutive weeks. Histopathological changes, the levels of cytokines and chemokines in the nasal lavage fluid, and immune cells of the blood and spleen were analyzed.

Results

The mice administered multiple allergens showed significantly increased eosinophil infiltration, epithelial thickening and disruption, and subepithelial collagen deposition from 8 weeks compared to the control group. Goblet cell hyperplasia, polyp-like lesions, and blood eosinophils, as well as the levels of interleukin-5 and eotaxin in the nasal lavage fluid were considerably increased in the ECRS group from 12 weeks compared to those of controls. Instillation of allergens for 16 weeks exacerbated the eosinophil infiltration and eotaxin increase in the nasal lavage fluid.

Conclusions

We successfully established a new murine model of ECRS using more clinically relevant multiple airborne allergens. Prolonged exposure to airborne allergens for 12 weeks or more, corresponding to the definition of human ECRS, strongly induced eosinophil infiltration as well as epithelial remodeling.

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Funding

This study was supported by the Bio & Medical Technology Development Program of the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT & Future Planning (MSIP) (2016M3A9D5A01952414), and the NRF grant funded by the Korean Government (MSIP) (2016R1A5A2008630). This research was also supported by the NRF Grant funded by the Korean Government (Ministry of Science and ICT) (NRF-2018R1C1B6007431).

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Author notes

  1. Sang Chul Park and Soo In Kim contributed equally to this work.

Authors and Affiliations

  1. Department of Otorhinolaryngology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea

    Sang Chul Park, Hyung-Ju Cho, Joo-Heon Yoon & Chang-Hoon Kim

  2. Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea

    Soo In Kim

  3. Korea Mouse Phenotyping Center, Seoul, South Korea

    Soo In Kim, Hyung-Ju Cho, Joo-Heon Yoon & Chang-Hoon Kim

  4. Department of Otorhinolaryngology, Yonsei University Wonju College of Medicine, Wonju, South Korea

    Chi Sang Hwang

  5. The Airway Mucus Institute, Yonsei University College of Medicine, Seoul, South Korea

    Hyung-Ju Cho, Joo-Heon Yoon & Chang-Hoon Kim

  6. Global Research Laboratory for Allergic Airway Diseases, Seoul, South Korea

    Joo-Heon Yoon

  7. Medical Research Center, Yonsei University College of Medicine, Seoul, South Korea

    Chang-Hoon Kim

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  1. Sang Chul Park
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Correspondence to Chang-Hoon Kim.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in this study involving animals were approved by the Ethics Committee and Institutional Animal Care and Use Committee of Yonsei University Health System (2017-0094), and the study was conducted according to international guidelines (ARRIVE) on animal experiments.

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405_2019_5465_MOESM1_ESM.tif

Supplementary material 1 (TIFF 17995 kb) Supplementary Fig. 1 Comparison of eosinophil infiltration between nine different areas of the nasal mucosa. Sirius red stain showing increased eosinophil infiltration in the ECRS group compared to that of controls in all areas measured, especially along the nasal septum (indicated areas 1, 2, 3, and 4), followed by the superior maxillary turbinate (indicated areas 5 and 6) and inferior maxillary turbinate (indicated areas 7 and 8). Data are expressed as means ± SD. * p < 0.05, ** p < 0.01, *** p < 0.001 between the control and ECRS groups. ECRS, eosinophilic chronic rhinosinusitis; HPF, high power fields

405_2019_5465_MOESM2_ESM.tif

Supplementary material 2 (TIFF 17481 kb) Supplementary Fig. 2 Comparison of goblet cell hyperplasia between nine different areas of the nasal mucosa. Periodic acid-Schiff stain showing increased goblet cell hyperplasia in the ECRS group compared to that of controls in all areas measured, especially in the nasal septum (indicated areas 2, 3, and 4) and superior maxillary turbinate (indicated area 6). Data are expressed as means ± SD. * p < 0.05 between the control and ECRS groups. ECRS, eosinophilic chronic rhinosinusitis; HPF, high power fields

405_2019_5465_MOESM3_ESM.tif

Supplementary material 3 (TIFF 13680 kb) Supplementary Fig. 3 Representative photomicrographs of epithelium disruption and formation of polyp-like lesions. a Hematoxylin and eosin-stained sections showing epithelial disruption only in the ECRS group from 8 weeks. b Sirius red stained section showing polyp-like lesions, defined as elevated mucosal lesions with eosinophilic infiltration and/or microcavity formation, which were detected only in the ECRS group from 12 weeks. (both panels: original magnification, ×400; magnified image of the ×40 figure on the left side; scale bar, 50 μm)

405_2019_5465_MOESM4_ESM.tif

Supplementary material 4 (TIFF 16476 kb) Supplementary Fig. 4 Flow cytometry gating strategy for analysis of neutrophils and eosinophils in the blood. Eosinophils (CD11c-, CD11b+, Ly-6G-, Siglec-F+) and neutrophils (CD11c-, CD11b+, Ly-6G+, Siglec-F-) were identified as shown

405_2019_5465_MOESM5_ESM.tif

Supplementary material 5 (TIFF 19800 kb) Supplementary Fig. 5 Flow cytometry gating strategy and immune cell analysis in the spleen at 16 weeks. a Flow cytometry gating scheme for analysis of immune cells to identify B cells (CD45+,CD11c-, MHC II+, CD19+), T cells (CD45+,CD11c-, MHC II-, CD3e+), dendritic cells (CD45+,CD11c+, MHC II+), and macrophages (CD45+,CD11c+, F4/80+, CD64+). b At 16 weeks, the percentage of spleen eosinophils among CD45+ cells was significantly elevated in the ECRS group compared to that of controls. *** p < 0.001 between the control and ECRS groups. ECRS, eosinophilic chronic rhinosinusitis

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Park, S.C., Kim, S.I., Hwang, C.S. et al. Multiple airborne allergen-induced eosinophilic chronic rhinosinusitis murine model. Eur Arch Otorhinolaryngol 276, 2273–2282 (2019). https://doi.org/10.1007/s00405-019-05465-x

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