{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T10:53:31Z","timestamp":1780916011013,"version":"3.54.1"},"reference-count":39,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2023,11,30]],"date-time":"2023-11-30T00:00:00Z","timestamp":1701302400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Education, Culture, Sports, Science and Technology of Japan","award":["19K07949"],"award-info":[{"award-number":["19K07949"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Eosinophilic airway inflammation, complicated by bronchial asthma and eosinophilic chronic rhinosinusitis (ECRS), is difficult to treat. The disease may become refractory when eosinophilic mucin associated with eosinophil peroxidase (EPX) and autoantibodies fills in the paranasal sinus and small airway. This study investigated the functional role of an anti-EPX antibody in eosinophilic mucin of ECRS in eosinophilic airway inflammation. Eosinophilic mucin was obtained from patients with ECRS. The effects of the anti-EPX antibody on dsDNA release from eosinophils and eosinophilic mucin decomposition were evaluated. Immunofluorescence or enzyme-linked immunosorbent assays were performed to detect the anti-EPX antibody and its supernatant and serum levels in eosinophilic mucin, respectively. The serum levels of the anti-EPX antibody were positively correlated with sinus computed tomography score and fractionated exhaled nitrogen oxide. Patients with refractory ECRS had higher serum levels of the anti-EPX antibody than those without. However, dupilumab treatment decreased the serum levels of the anti-EPX antibody. Immunoglobulins (Igs) in the immunoprecipitate of mucin supernatants enhanced dsDNA release from eosinophils, whereas the neutralization of Igs against EPX stopped dsDNA release. Furthermore, EPX antibody neutralization accelerated mucin decomposition and restored corticosteroid sensitivity. Taken together, the anti-EPX antibody may be involved in the formulation of eosinophilic mucin and be used as a clinical marker and therapeutic target for intractable eosinophilic airway inflammation.<\/jats:p>","DOI":"10.3390\/cells12232746","type":"journal-article","created":{"date-parts":[[2023,11,30]],"date-time":"2023-11-30T07:44:42Z","timestamp":1701330282000},"page":"2746","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The Neutralization of the Eosinophil Peroxidase Antibody Accelerates Eosinophilic Mucin Decomposition"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3755-3074","authenticated-orcid":false,"given":"Yoshiki","family":"Kobayashi","sequence":"first","affiliation":[{"name":"Airway Disease Section, Department of Otorhinolaryngology, Kansai Medical University, Osaka 573-1010, Japan"},{"name":"Allergy Center, Kansai Medical University Hospital, Osaka 573-1010, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanh Hong","family":"Chu","sequence":"additional","affiliation":[{"name":"Airway Disease Section, Department of Otorhinolaryngology, Kansai Medical University, Osaka 573-1010, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan Van","family":"Bui","sequence":"additional","affiliation":[{"name":"Airway Disease Section, Department of Otorhinolaryngology, Kansai Medical University, Osaka 573-1010, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6879-6303","authenticated-orcid":false,"given":"Yasutaka","family":"Yun","sequence":"additional","affiliation":[{"name":"Airway Disease Section, Department of Otorhinolaryngology, Kansai Medical University, Osaka 573-1010, Japan"},{"name":"Allergy Center, Kansai Medical University Hospital, Osaka 573-1010, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linh Manh","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Airway Disease Section, Department of Otorhinolaryngology, Kansai Medical University, Osaka 573-1010, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2062-5505","authenticated-orcid":false,"given":"Akitoshi","family":"Mitani","sequence":"additional","affiliation":[{"name":"Airway Disease Section, Department of Otorhinolaryngology, Kansai Medical University, Osaka 573-1010, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1659-1549","authenticated-orcid":false,"given":"Kensuke","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Airway Disease Section, Department of Otorhinolaryngology, Kansai Medical University, Osaka 573-1010, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikiya","family":"Asako","sequence":"additional","affiliation":[{"name":"Airway Disease Section, Department of Otorhinolaryngology, Kansai Medical University, Osaka 573-1010, Japan"},{"name":"Allergy Center, Kansai Medical University Hospital, Osaka 573-1010, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6324-721X","authenticated-orcid":false,"given":"Akira","family":"Kanda","sequence":"additional","affiliation":[{"name":"Airway Disease Section, Department of Otorhinolaryngology, Kansai Medical University, Osaka 573-1010, Japan"},{"name":"Allergy Center, Kansai Medical University Hospital, Osaka 573-1010, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2646-8173","authenticated-orcid":false,"given":"Hiroshi","family":"Iwai","sequence":"additional","affiliation":[{"name":"Airway Disease Section, Department of Otorhinolaryngology, Kansai Medical University, Osaka 573-1010, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"32","DOI":"10.4193\/Rhin17.255","article-title":"The Global Allergy and Asthma European Network (GALEN rhinosinusitis cohort: A large European cross-sectional study of chronic rhinosinusitis patients with and without nasal polyps","volume":"57","author":"Khan","year":"2019","journal-title":"Rhinology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.1016\/j.jaci.2016.05.041","article-title":"Diversity of T(H) cytokine profiles in patients with chronic rhinosinusitis: A multicenter study in Europe, Asia, and Oceania","volume":"138","author":"Wang","year":"2016","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.alit.2019.07.002","article-title":"Eosinophilic chronic rhinosinusitis","volume":"68","author":"Fujieda","year":"2019","journal-title":"Allergol. Int."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.3109\/00016489.2015.1063784","article-title":"Post-operative steroid treatment for eosinophilic-type sinonasal polyposis","volume":"135","author":"Brescia","year":"2015","journal-title":"Acta Otolaryngol."},{"key":"ref_5","first-page":"Cd011996","article-title":"Intranasal steroids versus placebo or no intervention for chronic rhinosinusitis","volume":"4","author":"Chong","year":"2016","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1002\/lary.23212","article-title":"Topical corticosteroids applied with a squirt system are more effective than a nasal spray for steroid-dependent olfactory impairment","volume":"122","author":"Shu","year":"2012","journal-title":"Laryngoscope"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1016\/j.jaci.2013.04.052","article-title":"Severe adult-onset asthma: A distinct phenotype","volume":"132","author":"Amelink","year":"2013","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1111\/all.12644","article-title":"Novel scoring system and algorithm for classifying chronic rhinosinusitis: The JESREC Study","volume":"70","author":"Tokunaga","year":"2015","journal-title":"Allergy"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"100600","DOI":"10.1016\/j.waojou.2021.100600","article-title":"Real-world benefits of biologics for asthma: Exacerbation events and systemic corticosteroid use","volume":"14","author":"Kimura","year":"2021","journal-title":"World Allergy Organ. J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1111\/all.14906","article-title":"Dupilumab efficacy in chronic rhinosinusitis with nasal polyps from SINUS-52 is unaffected by eosinophilic status","volume":"77","author":"Fujieda","year":"2022","journal-title":"Allergy"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Kobayashi, Y., Kanda, A., Yun, Y., Dan Van, B., Suzuki, K., Sawada, S., Asako, M., and Iwai, H. (2020). Reduced Local Response to Corticosteroids in Eosinophilic Chronic Rhinosinusitis with Asthma. Biomolecules, 10.","DOI":"10.3390\/biom10020326"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1056\/NEJMra2032506","article-title":"Biologic Therapies for Severe Asthma","volume":"386","author":"Brusselle","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2475","DOI":"10.1056\/NEJMoa1804093","article-title":"Efficacy and Safety of Dupilumab in Glucocorticoid-Dependent Severe Asthma","volume":"378","author":"Rabe","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"210144","DOI":"10.1183\/20734735.0144-2021","article-title":"A pragmatic guide to choosing biologic therapies in severe asthma","volume":"17","author":"Kavanagh","year":"2021","journal-title":"Breathe"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1638","DOI":"10.1016\/S0140-6736(19)31881-1","article-title":"Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): Results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials","volume":"394","author":"Bachert","year":"2019","journal-title":"Lancet"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1177\/1945892420943828","article-title":"Eosinophilic Mucin: A Predictor for Disease Severity in Chronic Rhinosinusitis","volume":"35","author":"Unsal","year":"2021","journal-title":"Am. J. Rhinol. Allergy"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1172\/JCI95693","article-title":"Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction","volume":"128","author":"Dunican","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2192","DOI":"10.3389\/fimmu.2018.02192","article-title":"HFA-BDP Metered-Dose Inhaler Exhaled Through the Nose Improves Eosinophilic Chronic Rhinosinusitis With Bronchial Asthma: A Blinded, Placebo-Controlled Study","volume":"9","author":"Kobayashi","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Kobayashi, Y., Kanda, A., Bui, D.V., Yun, Y., Nguyen, L.M., Chu, H.H., Mitani, A., Suzuki, K., Asako, M., and Iwai, H. (2021). Omalizumab Restores Response to Corticosteroids in Patients with Eosinophilic Chronic Rhinosinusitis and Severe Asthma. Biomedicines, 9.","DOI":"10.3390\/biomedicines9070787"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Kobayashi, Y., Mercado, N., Barnes, P.J., and Ito, K. (2011). Defects of protein phosphatase 2A causes corticosteroid insensitivity in severe asthma. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0027627"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.jaci.2015.04.041","article-title":"Eosinophil extracellular trap cell death-derived DNA traps: Their presence in secretions and functional attributes","volume":"137","author":"Ueki","year":"2016","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1083\/jcb.201203170","article-title":"Neutrophil extracellular traps: Is immunity the second function of chromatin?","volume":"198","author":"Brinkmann","year":"2012","journal-title":"J. Cell Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"9813","DOI":"10.1073\/pnas.0909927107","article-title":"Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis","volume":"107","author":"Hakkim","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1007\/s10157-012-0738-8","article-title":"Possible implication of disordered neutrophil extracellular traps in the pathogenesis of MPO-ANCA-associated vasculitis","volume":"17","author":"Nakazawa","year":"2013","journal-title":"Clin. Exp. Nephrol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"94","DOI":"10.4168\/aair.2023.15.1.94","article-title":"Effects of Neutrophil and Eosinophil Extracellular Trap Formation on Refractoriness in Chronic Rhinosinusitis With Nasal Polyps","volume":"15","author":"Cha","year":"2023","journal-title":"Allergy Asthma Immunol. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1016\/j.jaci.2011.08.037","article-title":"Evidence for intranasal antinuclear autoantibodies in patients with chronic rhinosinusitis with nasal polyps","volume":"128","author":"Tan","year":"2011","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1016\/j.jaci.2017.06.033","article-title":"Sputum autoantibodies in patients with severe eosinophilic asthma","volume":"141","author":"Mukherjee","year":"2018","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Chu, H.H., Kobayashi, Y., Bui, D.V., Yun, Y., Nguyen, L.M., Mitani, A., Suzuki, K., Asako, M., Kanda, A., and Iwai, H. (2022). CCL4 Regulates Eosinophil Activation in Eosinophilic Airway Inflammation. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232416149"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1136\/thx.24.6.707","article-title":"Rheological assessment of mucolytic agents on sputum of chronic bronchitics","volume":"24","author":"Dippy","year":"1969","journal-title":"Thorax"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1016\/S2213-2600(23)00230-8","article-title":"2023 GINA report for asthma","volume":"11","author":"Venkatesan","year":"2023","journal-title":"Lancet Respir. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1002\/(SICI)1099-0496(199803)25:3<167::AID-PPUL6>3.0.CO;2-J","article-title":"Serum eosinophil cationic protein (ECP) and eosinophil protein X (EPX) in childhood asthma: The influence of atopy","volume":"25","author":"Remes","year":"1998","journal-title":"Pediatr. Pulmonol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1007\/s000110050466","article-title":"Two eosinophil granule proteins, eosinophil peroxidase and major basic protein, inhibit mucin release from hamster tracheal surface epithelial cells in primary culture","volume":"48","author":"Kim","year":"1999","journal-title":"Inflamm. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3460","DOI":"10.4049\/jimmunol.151.7.3460","article-title":"Combination IL-2 and IL-4 reduces glucocorticoid receptor-binding affinity and T cell response to glucocorticoids","volume":"151","author":"Kam","year":"1993","journal-title":"J. Immunol. (Baltim. Md. 1950)"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Kobayashi, Y., Chu, H.H., Kanda, A., Yun, Y., Shimono, M., Nguyen, L.M., Mitani, A., Suzuki, K., Asako, M., and Iwai, H. (2022). CCL4 Functions as a Biomarker of Type 2 Airway Inflammation. Biomedicines, 10.","DOI":"10.3390\/biomedicines10081779"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1016\/j.jaci.2018.08.030","article-title":"Differential expression of functional chemokine receptors on human blood and lung group 2 innate lymphoid cells","volume":"143","author":"Weston","year":"2019","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.3389\/fimmu.2018.01445","article-title":"Anti-Allergic Inflammatory Activity of Interleukin-37 Is Mediated by Novel Signaling Cascades in Human Eosinophils","volume":"9","author":"Zhu","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"6092","DOI":"10.4049\/jimmunol.175.9.6092","article-title":"Differences in potency of CXC chemokine ligand 8-, CC chemokine ligand 11-, and C5a-induced modulation of integrin function on human eosinophils","volume":"175","author":"Ulfman","year":"2005","journal-title":"J. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1016\/j.jaci.2017.02.045","article-title":"Sputum transcriptomics reveal upregulation of IL-1 receptor family members in patients with severe asthma","volume":"141","author":"Rossios","year":"2018","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"718267","DOI":"10.3389\/falgy.2021.718267","article-title":"Immunobiology of Steroid-Unresponsive Severe Asthma","volume":"2","author":"Marshall","year":"2021","journal-title":"Front. Allergy"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/23\/2746\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:34:49Z","timestamp":1760132089000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/23\/2746"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,30]]},"references-count":39,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["cells12232746"],"URL":"https:\/\/doi.org\/10.3390\/cells12232746","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,30]]}}}