TY - JOUR
T1 - Characterization of a novel, papain-inducible murine model of eosinophilic rhinosinusitis
AU - Tharakan, Anuj
AU - Dobzanski, Alex
AU - London, Nyall R.
AU - Khalil, Syed M.
AU - Surya, Nitya
AU - Lane, Andrew P.
AU - Ramanathan, Murugappan
N1 - Funding Information:
Correspondence to: Murugappan Ramanathan Jr, MD, Department of Otolaryngology–Head and Neck Surgery, Johns Hopkins Outpatient Center, 601 North Caroline Street, 6th Floor, 6263, Baltimore, MD 21287; e-mail: [email protected] Funding source for the study: National Institutes of Health grants ES020859 (to M.R.) and AI072502 (to A.P.L.). Potential conflict of interest: N.R.L. is a patent co-inventor for methods treating vascular barrier dysfunction licensed to Navigen Pharmaceuticals, which is unrelated to papain and allergy, and holds a small amount of stock in Navigen Pharmaceuticals, which currently has no value. Presented at the ARS meeting at the American Academy of Otolaryngology–Head Neck Surgery, on September 8–9, 2017 in Chicago, IL.
Publisher Copyright:
© 2018 ARS-AAOA, LLC
PY - 2018/4
Y1 - 2018/4
N2 - Background: Eosinophilic chronic rhinosinusitis (ECRS) is a disease characterized by eosinophilic inflammatory infiltrate and a local type 2 cytokine milieu. Current animal models fail to recapitulate many of the innate and adaptive immunologic hallmarks of the disease, thus hindering the development of effective therapeutics. In the present study, mice were exposed intranasally to the cysteine protease papain, which shares functional similarities with parasitic proteases and aeroallergens, to generate a rapidly inducible murine model of eosinophilic rhinosinusitis. Methods: C57BL/6 mice were intranasally instilled with 20 μg papain or heat-inactivated papain (HP) on days 0–2 and days 7–10, and then euthanized on day 11. Nasal lavage fluid (NALF) was analyzed to quantify eosinophils and inflammatory cytokine secretion. Sinonasal tissue was sectioned and stained for goblet cells or homogenized to analyze cytokine levels. Serum samples were assayed for immunoglobulin E (IgE) by enzyme-linked immunoassay. Sinonasal mucosal tissue was dissociated and analyzed by flow cytometry. Results: Compared with HP treatment, papain induced significant eosinophilia in NALF, goblet cell hyperplasia, innate and adaptive immune cell infiltration, type 2 cytokine production, and IgE responses. Flow cytometric analysis of sinonasal tissues revealed significant inflammatory cell infiltration and interleukin-13–producing cell populations. Conclusion: In this study, we demonstrated that the cysteine protease papain induces allergic sinonasal eosinophilic rhinosinusitis and resembles T-helper 2 cell inflammation and innate immune characteristics of ECRS. This model permits further study into the molecular mechanisms underlying ECRS pathology and provides a model system for the evaluation of potential pharmacologic interventions.
AB - Background: Eosinophilic chronic rhinosinusitis (ECRS) is a disease characterized by eosinophilic inflammatory infiltrate and a local type 2 cytokine milieu. Current animal models fail to recapitulate many of the innate and adaptive immunologic hallmarks of the disease, thus hindering the development of effective therapeutics. In the present study, mice were exposed intranasally to the cysteine protease papain, which shares functional similarities with parasitic proteases and aeroallergens, to generate a rapidly inducible murine model of eosinophilic rhinosinusitis. Methods: C57BL/6 mice were intranasally instilled with 20 μg papain or heat-inactivated papain (HP) on days 0–2 and days 7–10, and then euthanized on day 11. Nasal lavage fluid (NALF) was analyzed to quantify eosinophils and inflammatory cytokine secretion. Sinonasal tissue was sectioned and stained for goblet cells or homogenized to analyze cytokine levels. Serum samples were assayed for immunoglobulin E (IgE) by enzyme-linked immunoassay. Sinonasal mucosal tissue was dissociated and analyzed by flow cytometry. Results: Compared with HP treatment, papain induced significant eosinophilia in NALF, goblet cell hyperplasia, innate and adaptive immune cell infiltration, type 2 cytokine production, and IgE responses. Flow cytometric analysis of sinonasal tissues revealed significant inflammatory cell infiltration and interleukin-13–producing cell populations. Conclusion: In this study, we demonstrated that the cysteine protease papain induces allergic sinonasal eosinophilic rhinosinusitis and resembles T-helper 2 cell inflammation and innate immune characteristics of ECRS. This model permits further study into the molecular mechanisms underlying ECRS pathology and provides a model system for the evaluation of potential pharmacologic interventions.
KW - IL-33
KW - epithelial barrier
KW - papain
KW - rhinosinusitis
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U2 - 10.1002/alr.22072
DO - 10.1002/alr.22072
M3 - Article
C2 - 29341450
AN - SCOPUS:85040723715
SN - 2042-6976
VL - 8
SP - 513
EP - 521
JO - International Forum of Allergy and Rhinology
JF - International Forum of Allergy and Rhinology
IS - 4
ER -