{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T23:45:00Z","timestamp":1789170300898,"version":"build-2803163510"},"reference-count":139,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,4,17]],"date-time":"2023-04-17T00:00:00Z","timestamp":1681689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Chronic rhinosinusitis (CRS) is a clinical syndrome primarily characterized by long-term mucosal inflammation of the nasal cavity and sinuses. The pathogenesis of CRS is still unclear due to its high heterogeneity. A number of studies have recently focused on the sinonasal epithelium. Thus, there has been a quantum leap in awareness of the role of the sinonasal epithelium, which is now understood as an active functional organ rather than simply an inert mechanical barrier. Undoubtedly, epithelial dysfunction plays a vital role in the onset and development of CRS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>In this article, we discuss the potential contribution of sinonasal epithelium dysfunction to CRS pathogenesis and explore a few current and developing therapeutic options targeting the sinonasal epithelium.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Impaired mucociliary clearance (MCC) and an abnormal sinonasal epithelial barrier are usually considered to be the main causative factors in CRS. Epithelial-derived bioactive substances, such as cytokines, exosomes, and complements, play a vital role in the regulation of innate and adaptive immunity and contribute to the pathophysiological alterations of CRS. The phenomena of epithelial\u2013mesenchymal transition (EMT), mucosal remodeling, and autophagy observed in CRS offer some novel insights into the pathogenesis of this disease. In addition, existing treatment options targeting disorder of sinonasal epithelium can help to relieve the main symptoms associated with CRS to some extent.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The presence of a normal epithelium is fundamental for maintaining homeostasis in the nasal and paranasal sinuses. Here, we describe various aspects of the sinonasal epithelium and highlight the contributions of epithelial dysfunction to CRS pathogenesis. Our review provides sound evidence of the need for in-depth study of the pathophysiological alterations of this disease and for the development of novel epithelium-targeting alternative treatments.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fmed.2023.1139240","type":"journal-article","created":{"date-parts":[[2023,4,17]],"date-time":"2023-04-17T05:34:01Z","timestamp":1681709641000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":26,"title":["Pathogenesis and treatment of chronic rhinosinusitis from the perspective of sinonasal epithelial dysfunction"],"prefix":"10.3389","volume":"10","author":[{"given":"Yuanqiong","family":"He","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yijie","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqi","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianmin","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,4,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1080\/1744666X.2019.1601556","article-title":"Epithelial physical barrier defects in chronic rhinosinusitis","volume":"15","author":"Jiao","year":"2019","journal-title":"Expert Rev Clin Immu"},{"key":"B2","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1146\/annurev-pathol-052016-100401","article-title":"Immunopathogenesis of chronic rhinosinusitis and nasal polyposis","volume":"24","author":"Schleimer","year":"2017","journal-title":"Annu Rev Pathol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1007\/s11882-015-0540-2","article-title":"The etiology and pathogenesis of chronic rhinosinusitis: a review of current hypotheses","volume":"15","author":"Lam","year":"2015","journal-title":"Curr Allergy Asthma Rep."},{"key":"B4","doi-asserted-by":"publisher","first-page":"102587","DOI":"10.1016\/j.amjoto.2020.102587","article-title":"Type 1\/type 2 inflammatory cytokines correlate with olfactory function in patients with chronic rhinosinusitis","volume":"41","author":"Han","year":"2020","journal-title":"Am J Otolaryng."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1254","DOI":"10.1016\/j.jaci.2019.06.023","article-title":"Cross-talk between T(H)2 and T(H)17 pathways in patients with chronic rhinosinusitis with nasal polyps","volume":"144","author":"Wang","year":"2019","journal-title":"J Allergy Clin Immunol."},{"key":"B6","doi-asserted-by":"publisher","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":"B7","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1111\/cea.12712","article-title":"Chronic inflammatory airway diseases: the central role of the epithelium revisited","volume":"46","author":"Gohy","year":"2016","journal-title":"Clin Exp Allergy"},{"key":"B8","doi-asserted-by":"publisher","first-page":"691227","DOI":"10.3389\/fphys.2021.691227","article-title":"Epithelial barrier dysfunction in chronic respiratory diseases","volume":"12","author":"Carlier","year":"2021","journal-title":"Front Physiol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1111\/cea.13539","article-title":"Key role of the epithelium in chronic upper airways diseases","volume":"50","author":"Gohy","year":"2020","journal-title":"Clin Exp Allergy"},{"key":"B10","doi-asserted-by":"publisher","first-page":"6012","DOI":"10.3390\/ijms20236012","article-title":"Reciprocal association between the apical junctional complex and ampk: a promising therapeutic target for epithelial\/endothelial barrier function?","volume":"20","author":"Tsukita","year":"2019","journal-title":"Int J Mol Sci."},{"key":"B11","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1089\/jamp.2007.0659","article-title":"Role of cilia, mucus, and airway surface liquid in mucociliary dysfunction: lessons from mouse models","volume":"21","author":"Mall","year":"2008","journal-title":"J Aerosol Med Pulmon Drug Delivery."},{"key":"B12","doi-asserted-by":"publisher","first-page":"663626","DOI":"10.3389\/fimmu.2021.663626","article-title":"Nasal epithelial barrier integrity and tight junctions disruption in allergic rhinitis: overview and pathogenic insights","volume":"12","author":"Nur Husna","year":"2021","journal-title":"Front Immunol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"482","DOI":"10.4168\/aair.2019.11.4.482","article-title":"Comparison of corticosteroids by 3 approaches to the treatment of chronic rhinosinusitis with nasal polyps","volume":"11","author":"Zhang","year":"2019","journal-title":"Allergy Asthma Immun"},{"key":"B14","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1016\/j.bjorl.2020.03.008","article-title":"Efficacy of nasal irrigation with hypertonic saline on chronic rhinosinusitis: systematic review and meta-analysis","volume":"86","author":"Liu","year":"2020","journal-title":"Braz J Otorhinolaryngol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"126","DOI":"10.4193\/Rhin19.184","article-title":"Long-term outcomes of different endoscopic sinus surgery in recurrent chronic rhinosinusitis with nasal polyps and asthma","volume":"58","author":"Zhang","year":"2020","journal-title":"Rhinology."},{"key":"B16","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1177\/0194599820939964","article-title":"Role of biologics in chronic rhinosinusitis with nasal polyposis: state of the art review","volume":"164","author":"Kim","year":"2021","journal-title":"Otolaryngol Head Neck Surg."},{"key":"B17","doi-asserted-by":"publisher","first-page":"183316","DOI":"10.1016\/j.bbamem.2020.183316","article-title":"Cell-cell junctions as sensors and transducers of mechanical forces","volume":"1862","author":"Angulo-Urarte","year":"2020","journal-title":"Biochim Biophys Acta Biomembranes."},{"key":"B18","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1016\/j.bbamem.2007.07.012","article-title":"Adherens and tight junctions: structure, function and connections to the actin cytoskeleton","volume":"1778","author":"Hartsock","year":"2008","journal-title":"Biochim Biophys Acta."},{"key":"B19","doi-asserted-by":"publisher","first-page":"17026","DOI":"10.1038\/nrdp.2017.26","article-title":"Pemphigus","volume":"3","author":"Kasperkiewicz","year":"2017","journal-title":"Nat Rev Dis Primers."},{"key":"B20","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1159\/000362246","article-title":"The expression of epithelial intercellular junctional proteins in the sinonasal tissue of subjects with chronic rhinosinusitis: a histopathologic study","volume":"76","author":"Li","year":"2014","journal-title":"ORL"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1087","DOI":"10.1016\/j.jaci.2012.05.052","article-title":"Defective epithelial barrier in chronic rhinosinusitis: the regulation of tight junctions by IFN-\u03b3 and IL-4","volume":"130","author":"Soyka","year":"2012","journal-title":"J Allergy Clin Immunol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1145","DOI":"10.1002\/alr.21827","article-title":"Reversal of cigarette smoke extract-induced sinonasal epithelial cell barrier dysfunction through Nrf2 activation","volume":"6","author":"Tharakan","year":"2016","journal-title":"Int Forum Allergy Rhinol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1038\/cdd.2017.14","article-title":"AMPK improves gut epithelial differentiation and barrier function via regulating Cdx2 expression","volume":"24","author":"Sun","year":"2017","journal-title":"Cell Death Differ."},{"key":"B24","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1159\/000516847","article-title":"Eosinophils correlate with epithelial-mesenchymal transition in chronic rhinosinusitis with nasal polyps","volume":"84","author":"Wang","year":"2022","journal-title":"ORL"},{"key":"B25","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1002\/iid3.161","article-title":"Group 2 innate lymphoid cells are elevated and activated in chronic rhinosinusitis with nasal polyps","volume":"5","author":"Poposki","year":"2017","journal-title":"Immunity Inflamm Dis."},{"key":"B26","doi-asserted-by":"publisher","first-page":"e0139945","DOI":"10.1371\/journal.pone.0139945","article-title":"Non-eosinophilic nasal polyps shows increased epithelial proliferation and localized disease pattern in the early stage","volume":"10","author":"Kim","year":"2015","journal-title":"PLoS ONE."},{"key":"B27","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1111\/cea.12644","article-title":"Role of IFN-\u03b3, IL-13, and IL-17 on mucociliary differentiation of nasal epithelial cells in chronic rhinosinusitis with nasal polyps","volume":"46","author":"Jiao","year":"2016","journal-title":"Clin Exp Allergy"},{"key":"B28","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1080\/15548627.2015.1056967","article-title":"IL13 activates autophagy to regulate secretion in airway epithelial cells","volume":"12","author":"Dickinson","year":"2016","journal-title":"Autophagy."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1043","DOI":"10.1016\/j.jaci.2015.10.050","article-title":"Impaired barrier function in patients with house dust mite-induced allergic rhinitis is accompanied by decreased occludin and zonula occludens-1 expression","volume":"137","author":"Steelant","year":"2016","journal-title":"J Allergy Clin Immunol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"56","DOI":"10.4168\/aair.2020.12.1.56","article-title":"Particulate matter 2.5 causes deficiency in barrier integrity in human nasal epithelial cells","volume":"12","author":"Xian","year":"2020","journal-title":"Allergy Asthma Immunol Res"},{"key":"B31","doi-asserted-by":"publisher","first-page":"678","DOI":"10.1002\/jat.3573","article-title":"Nasal epithelial barrier disruption by particulate matter \u2264 2.5 \u03bcm via tight junction protein degradation","volume":"38","author":"Zhao","year":"2018","journal-title":"J Appl Toxicol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1620\/tjem.239.117","article-title":"Airborne fine particulate matter induces oxidative stress and inflammation in human nasal epithelial cells","volume":"239","author":"Hong","year":"2016","journal-title":"Tohoku J Exp Med."},{"key":"B33","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1111\/cea.13760","article-title":"Staphylococcus aureus enterotoxin B disrupts nasal epithelial barrier integrity","volume":"51","author":"Martens","year":"2021","journal-title":"Clin Exp Allergy"},{"key":"B34","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.alit.2017.08.011","article-title":"Role of airway epithelial barrier dysfunction in pathogenesis of asthma","volume":"67","author":"Gon","year":"2018","journal-title":"Allergol Int."},{"key":"B35","doi-asserted-by":"publisher","first-page":"S143","DOI":"10.1513\/AnnalsATS.201802-128AW","article-title":"Airway epithelial differentiation and mucociliary clearance","volume":"15","author":"Whitsett","year":"2018","journal-title":"Ann Am Thorac Soc."},{"key":"B36","doi-asserted-by":"publisher","first-page":"L603","DOI":"10.1152\/ajplung.00283.2020","article-title":"First contact: the role of respiratory cilia in host-pathogen interactions in the airways","volume":"319","author":"Kuek","year":"2020","journal-title":"Am J Physiol Lung Cell Mol Physiol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1127","DOI":"10.1007\/s00424-019-02280-5","article-title":"Ciliary beating amplitude controlled by intracellular Cl(-) and a high rate of CO(2) production in ciliated human nasal epithelial cells","volume":"471","author":"Inui","year":"2019","journal-title":"Pflugers Arch Eur J Physiol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"3754","DOI":"10.3390\/ijms19123754","article-title":"Daidzein-stimulated increase in the ciliary beating amplitude via an [Cl(-)](i) decrease in ciliated human nasal epithelial cells","volume":"19","author":"Inui","year":"2018","journal-title":"Int J Mol Sci."},{"key":"B39","doi-asserted-by":"publisher","first-page":"830","DOI":"10.1177\/1945892420930975","article-title":"Differential chloride secretory capacity in transepithelial ion transport properties in chronic rhinosinusitis","volume":"34","author":"McCormick","year":"2020","journal-title":"Am J Rhinol Allergy"},{"key":"B40","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1016\/j.jaci.2020.06.037","article-title":"Proteomic analysis of nasal mucus samples of healthy patients and patients with chronic rhinosinusitis","volume":"147","author":"Kao","year":"2021","journal-title":"J Allergy Clin Immunol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1186\/s13223-020-00440-2","article-title":"Epidermal growth factor upregulates expression of MUC5AC via TMEM16A, in chronic rhinosinusitis with nasal polyps","volume":"16","author":"Jiao","year":"2020","journal-title":"Allergy Asthma Clin Immul"},{"key":"B42","first-page":"454","article-title":"Expression and significance of eosinophil basic proteins in nasal mucus of chronic sinusitis","volume":"10","author":"Hou","year":"2008","journal-title":"J Clin Otorhinolaryngol Head Neck Surg."},{"key":"B43","doi-asserted-by":"publisher","first-page":"1053","DOI":"10.13201\/j.issn.2096-7993.2020.11.024","article-title":"The role of epithelial cells in the formation and development of nasal polyps","volume":"34","author":"Chen","year":"2020","journal-title":"J Clin Otorhinolaryngol Head Neck Surg."},{"key":"B44","doi-asserted-by":"publisher","first-page":"478","DOI":"10.1016\/j.jaci.2009.05.017","article-title":"Distinct immunopathologic characteristics of various types of chronic rhinosinusitis in adult Chinese","volume":"124","author":"Cao","year":"2009","journal-title":"J Allergy Clin Immunol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"3969","DOI":"10.2147\/JIR.S322875","article-title":"Necroptosis underlies neutrophilic inflammation associated with the chronic rhinosinusitis with nasal polyps (CRSwNP)","volume":"14","author":"Xie","year":"2021","journal-title":"J Inflamm Res"},{"key":"B46","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1097\/ACI.0000000000000588","article-title":"Th2 inflammatory responses in the development of nasal polyps and chronic rhinosinusitis","volume":"20","author":"Ryu","year":"2020","journal-title":"Curr Opin Allergy Clin Immunol"},{"key":"B47","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1186\/s13601-018-0237-4","article-title":"Elevated expression of IL-17RB and ST2 on myeloid dendritic cells is associated with a Th2-skewed eosinophilic inflammation in nasal polyps","volume":"8","author":"Zheng","year":"2018","journal-title":"Clin Transl Allergy"},{"key":"B48","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1002\/alr.22206","article-title":"Sentinels at the wall: epithelial-derived cytokines serve as triggers of upper airway type 2 inflammation","volume":"9","author":"Patel","year":"2019","journal-title":"Int Forum Allergy Rhinol"},{"key":"B49","doi-asserted-by":"publisher","first-page":"1169","DOI":"10.1111\/all.12667","article-title":"Interaction of thymic stromal lymphopoietin, IL-33, and their receptors in epithelial cells in eosinophilic chronic rhinosinusitis with nasal polyps","volume":"70","author":"Liao","year":"2015","journal-title":"Allergy."},{"key":"B50","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1016\/j.jaci.2009.10.072","article-title":"Evidence for altered activity of the IL-6 pathway in chronic rhinosinusitis with nasal polyps","volume":"125","author":"Peters","year":"2010","journal-title":"J Allergy Clin Immunol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"1830","DOI":"10.1002\/eji.201040391","article-title":"IL-6: regulator of Treg\/Th17 balance","volume":"40","author":"Kimura","year":"2010","journal-title":"Eur J Immunol"},{"key":"B52","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1186\/s12967-020-02309-9","article-title":"Pathogenesis of chronic rhinosinusitis with nasal polyps: role of IL-6 in airway epithelial cell dysfunction","volume":"18","author":"Bequignon","year":"2020","journal-title":"J Transl Med."},{"key":"B53","doi-asserted-by":"publisher","first-page":"3684","DOI":"10.7150\/thno.41580","article-title":"Progress, opportunity, and perspective on exosome isolation - efforts for efficient exosome-based theranostics","volume":"10","author":"Yang","year":"2020","journal-title":"Theranostics."},{"key":"B54","doi-asserted-by":"publisher","first-page":"812920","DOI":"10.3389\/fcimb.2021.812920","article-title":"The role of exosomes in the pathophysiology of chronic rhinosinusitis","volume":"11","author":"Mueller","year":"2021","journal-title":"Front Cell Infect Microbiol."},{"key":"B55","doi-asserted-by":"publisher","first-page":"328","DOI":"10.4193\/Rhin20.564","article-title":"Mucin 5AC is significantly upregulated in exosomes from the nasal lavage fluid and may promote the expression of COX-2, VEGF and MMP-9: an implication in nasal polyp pathogenesis","volume":"59","author":"Wang","year":"2021","journal-title":"Rhinology."},{"key":"B56","doi-asserted-by":"publisher","first-page":"1525","DOI":"10.1016\/j.jaci.2018.08.046","article-title":"Exosome swarms eliminate airway pathogens and provide passive epithelial immunoprotection through nitric oxide","volume":"143","author":"Nocera","year":"2019","journal-title":"J Allergy Clin Immunol."},{"key":"B57","doi-asserted-by":"publisher","first-page":"E295","DOI":"10.1002\/lary.26614","article-title":"Exosomes mediate interepithelial transfer of functional P-glycoprotein in chronic rhinosinusitis with nasal polyps","volume":"127","author":"Nocera","year":"2017","journal-title":"Laryngoscope"},{"key":"B58","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1186\/s12967-016-0927-4","article-title":"Exosomes in the nose induce immune cell trafficking and harbour an altered protein cargo in chronic airway inflammation","volume":"14","author":"L\u00e4sser","year":"2016","journal-title":"J Transl Med."},{"key":"B59","doi-asserted-by":"publisher","first-page":"726","DOI":"10.1080\/08820139.2020.1748047","article-title":"Exosomes represent an immune suppressive T cell checkpoint in human chronic inflammatory microenvironments","volume":"49","author":"Shenoy","year":"2020","journal-title":"Immunol Investig."},{"key":"B60","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1002\/alr.22226","article-title":"Noninvasive exosomal proteomic biosignatures, including cystatin SN, peroxiredoxin-5, and glycoprotein VI, accurately predict chronic rhinosinusitis with nasal polyps","volume":"9","author":"Mueller","year":"2019","journal-title":"Int Forum Allergy Rhinol"},{"key":"B61","doi-asserted-by":"publisher","first-page":"1069","DOI":"10.1002\/alr.22380","article-title":"Discriminant analysis followed by unsupervised cluster analysis including exosomal cystatins predict presence of chronic rhinosinusitis, phenotype, and disease severity","volume":"9","author":"Miyake","year":"2019","journal-title":"Int Forum Allergy Rhinol"},{"key":"B62","doi-asserted-by":"publisher","first-page":"1212","DOI":"10.1002\/alr.22407","article-title":"Escalation in mucus cystatin 2, pappalysin-A, and periostin levels over time predict need for recurrent surgery in chronic rhinosinusitis with nasal polyps","volume":"9","author":"Mueller","year":"2019","journal-title":"Int Forum Allergy Rhinol"},{"key":"B63","doi-asserted-by":"publisher","first-page":"1438","DOI":"10.1002\/alr.22189","article-title":"Highly multiplexed proteomic analysis reveals significant tissue and exosomal coagulation pathway derangement in chronic rhinosinusitis with nasal polyps","volume":"8","author":"Mueller","year":"2018","journal-title":"Int Forum Allergy Rhinol"},{"key":"B64","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1146\/annurev-immunol-032713-120154","article-title":"Complement and its receptors: new insights into human disease","volume":"32","author":"Holers","year":"2014","journal-title":"Annu Rev Immunol."},{"key":"B65","doi-asserted-by":"publisher","first-page":"e47383","DOI":"10.1371\/journal.pone.0047383","article-title":"Complement defects in patients with chronic rhinosinusitis","volume":"7","author":"Gaunsbaek","year":"2012","journal-title":"PLoS ONE."},{"key":"B66","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1159\/000504195","article-title":"Prognostic significance of serum complement component 3 in chronic rhinosinusitis with nasal polyps","volume":"82","author":"Wang","year":"2020","journal-title":"ORL"},{"key":"B67","doi-asserted-by":"publisher","first-page":"1909","DOI":"10.1016\/j.intimp.2007.07.006","article-title":"The role of the complement anaphylatoxins in the recruitment of eosinophils","volume":"7","author":"DiScipio","year":"2007","journal-title":"Int Immunopharmacol."},{"key":"B68","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1002\/alr.21704","article-title":"Vitamin D deficiency is associated with increased human sinonasal fibroblast proliferation in chronic rhinosinusitis with nasal polyps","volume":"6","author":"Carroll","year":"2016","journal-title":"Int Forum Allergy Rhinol"},{"key":"B69","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1002\/alr.21852","article-title":"Vitamin D pathway regulatory genes encoding 1\u03b1-hydroxylase and 24-hydroxylase are dysregulated in sinonasal tissue during chronic rhinosinusitis","volume":"7","author":"Christensen","year":"2017","journal-title":"Int Forum Allergy Rhinol"},{"key":"B70","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1002\/alr.21576","article-title":"Reduced sinonasal levels of 1\u03b1-hydroxylase are associated with worse quality of life in chronic rhinosinusitis with nasal polyps","volume":"6","author":"Schlosser","year":"2016","journal-title":"Int Forum Allergy Rhinol"},{"key":"B71","doi-asserted-by":"publisher","first-page":"e0186374","DOI":"10.1371\/journal.pone.0186374","article-title":"Dietary vitamin D3 deficiency exacerbates sinonasal inflammation and alters local 25(OH)D3 metabolism","volume":"12","author":"Mulligan","year":"2017","journal-title":"PLoS ONE"},{"key":"B72","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1016\/j.jaci.2015.12.1329","article-title":"Vitamin D3 therapy in patients with asthma complicated by sinonasal disease: Secondary analysis of the Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness in Asthma trial","volume":"138","author":"Jiao","year":"2016","journal-title":"J Allergy Clin Immunol."},{"key":"B73","doi-asserted-by":"publisher","first-page":"262","DOI":"10.4049\/jimmunol.2000726","article-title":"Role of C3a as a novel regulator of 25(OH)D(3) to 1\u03b1,25-dihydroxyvitamin D(3) metabolism in upper airway epithelial cells","volume":"209","author":"Mulligan","year":"2022","journal-title":"J Immunol."},{"key":"B74","doi-asserted-by":"publisher","first-page":"108984","DOI":"10.1016\/j.abb.2021.108984","article-title":"Molecular mechanism involved in epithelial to mesenchymal transition","volume":"710","author":"Jayachandran","year":"2021","journal-title":"Arch Biochem Biophys."},{"key":"B75","doi-asserted-by":"publisher","first-page":"1438","DOI":"10.1172\/JCI38019","article-title":"Epithelial-mesenchymal transitions: the importance of changing cell state in development and disease","volume":"119","author":"Acloque","year":"2009","journal-title":"J Clin Invest."},{"key":"B76","doi-asserted-by":"publisher","first-page":"941608","DOI":"10.3389\/fimmu.2022.941608","article-title":"TIM-4 in macrophages contributes to nasal polyp formation through the TGF-\u03b21-mediated epithelial to mesenchymal transition in nasal epithelial cells","volume":"13","author":"Qin","year":"2022","journal-title":"Front Immunol."},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.12932\/ap-040921-1224","article-title":"TGF-\u03b21 induces epithelial-to-mesenchymal transition in chronic rhinosinusitis with nasal polyps through microRNA-182","author":"Jiang","year":"2021","journal-title":"Asian Pac J Allergy Immunol."},{"key":"B78","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1159\/000497829","article-title":"TGF-\u03b21 induces epithelial-mesenchymal transition of chronic sinusitis with nasal polyps through microRNA-21","volume":"179","author":"Li","year":"2019","journal-title":"Int Arch Allergy Immunol."},{"key":"B79","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1165\/rcmb.2016-0024OC","article-title":"Wnt signaling in chronic rhinosinusitis with nasal polyps","volume":"56","author":"B\u00f6scke","year":"2017","journal-title":"Am J Respir Cell Mol Biol."},{"key":"B80","doi-asserted-by":"publisher","first-page":"982","DOI":"10.1136\/thoraxjnl-2019-213916","article-title":"Effects of Wnt signaling on epithelial to mesenchymal transition in chronic rhinosinusitis with nasal polyp","volume":"75","author":"Bae","year":"2020","journal-title":"Thorax."},{"key":"B81","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1097\/ACI.0b013e32835ad09e","article-title":"Mucosal remodeling and reversibility in chronic rhinosinusitis","volume":"13","author":"Bassiouni","year":"2013","journal-title":"Curr Opin Allergy Clin Immunol"},{"key":"B82","doi-asserted-by":"publisher","first-page":"910","DOI":"10.3390\/ijms22020910","article-title":"Advances in the knowledge of the underlying airway remodeling mechanisms in chronic rhinosinusitis based on the endotypes: a review","volume":"22","author":"Lee","year":"2021","journal-title":"Int J Mol Sci."},{"key":"B83","doi-asserted-by":"publisher","first-page":"835","DOI":"10.1002\/alr.21754","article-title":"Clinical implications of mucosal remodeling from chronic rhinosinusitis","volume":"6","author":"Do","year":"2016","journal-title":"Int Forum Allergy Rhinol"},{"key":"B84","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1002\/alr.21546","article-title":"Remodeling changes of the upper airway with chronic rhinosinusitis","volume":"5","author":"Barham","year":"2015","journal-title":"Int Forum Allergy Rhinol."},{"key":"B85","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1093\/intimm\/dxy061","article-title":"Eosinophil-derived neurotoxin enhances airway remodeling in eosinophilic chronic rhinosinusitis and correlates with disease severity","volume":"31","author":"Tsuda","year":"2019","journal-title":"Int Immunol."},{"key":"B86","doi-asserted-by":"publisher","first-page":"4195","DOI":"10.1242\/jcs.023820","article-title":"The extracellular matrix at a glance","volume":"123","author":"Frantz","year":"2010","journal-title":"J Cell Sci."},{"key":"B87","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/j.jaci.2006.02.046","article-title":"Periostin: a novel component of subepithelial fibrosis of bronchial asthma downstream of IL-4 and IL-13 signals","volume":"118","author":"Takayama","year":"2006","journal-title":"J Allergy Clin Immunol."},{"key":"B88","doi-asserted-by":"publisher","first-page":"234","DOI":"10.4193\/Rhino16.215","article-title":"Periostin as a marker of mucosal remodelling in chronic rhinosinusitis","volume":"55","author":"Ebenezer","year":"2017","journal-title":"Rhinology"},{"key":"B89","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1046\/j.1398-9995.2003.00364.x","article-title":"Matrix metalloproteinases MMP-7, MMP-9 and their tissue inhibitor TIMP-1: expression in chronic sinusitis vs nasal polyposis","volume":"59","author":"Watelet","year":"2004","journal-title":"Allergy"},{"key":"B90","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1016\/j.jaci.2009.04.013","article-title":"TGF-beta signaling and collagen deposition in chronic rhinosinusitis","volume":"124","author":"Van Bruaene","year":"2009","journal-title":"J Allergy Clin Immunol."},{"key":"B91","doi-asserted-by":"publisher","first-page":"1337","DOI":"10.3389\/fimmu.2020.01337","article-title":"Role of autophagy in lung inflammation","volume":"11","author":"Painter","year":"2020","journal-title":"Front Immunol."},{"key":"B92","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.cell.2007.12.018","article-title":"Autophagy in the pathogenesis of disease","volume":"132","author":"Levine","year":"2008","journal-title":"Cell"},{"key":"B93","doi-asserted-by":"publisher","first-page":"875","DOI":"10.1038\/s41419-019-2111-2","article-title":"Airway epithelial regeneration requires autophagy and glucose metabolism","volume":"10","author":"Li","year":"2019","journal-title":"Cell Death Dis."},{"key":"B94","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1080\/15548627.2015.1124224","article-title":"Autophagy is essential for ultrafine particle-induced inflammation and mucus hyperproduction in airway epithelium","volume":"12","author":"Chen","year":"2016","journal-title":"Autophagy"},{"key":"B95","doi-asserted-by":"publisher","first-page":"816","DOI":"10.1177\/19458924221116939","article-title":"HNE induces the hyperexpression of MUC5AC in chronic rhinosinusitis with nasal polyps by activating the TRAF6\/autophagy regulatory axis","volume":"36","author":"Zhang","year":"2022","journal-title":"Am J Rhinol Allergy"},{"key":"B96","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1016\/j.intimp.2019.03.028","article-title":"The role of autophagy in the overexpression of MUC5AC in patients with chronic rhinosinusitis","volume":"71","author":"Ye","year":"2019","journal-title":"Int Immunopharmacol."},{"key":"B97","doi-asserted-by":"publisher","first-page":"2273121","DOI":"10.1155\/2022\/2273121","article-title":"The roles of autophagy, mitophagy, and the Akt\/mTOR pathway in the pathogenesis of chronic rhinosinusitis with nasal polyps","volume":"2022","author":"Wang","year":"2022","journal-title":"J Immunol Res."},{"key":"B98","doi-asserted-by":"publisher","first-page":"938","DOI":"10.1016\/j.jaci.2017.10.038","article-title":"Autophagy deficiency in myeloid cells exacerbates eosinophilic inflammation in chronic rhinosinusitis","volume":"141","author":"Choi","year":"2018","journal-title":"J Allergy Clin Immunol."},{"key":"B99","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1002\/msc.1603","article-title":"The systemic immunosuppressive effects of peripheral corticosteroid injections: a narrative review of the evidence in the context of COVID-19","volume":"20","author":"Regan","year":"2022","journal-title":"Musculoskeletal Care."},{"key":"B100","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1016\/j.iac.2009.07.001","article-title":"Corticosteroid treatment in chronic rhinosinusitis: the possibilities and the limits","volume":"29","author":"Mullol","year":"2009","journal-title":"Immunol Allergy Clinics North Am."},{"key":"B101","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1002\/alr.22093","article-title":"Corticosteroid nasal irrigations are more effective than simple sprays in a randomized double-blinded placebo-controlled trial for chronic rhinosinusitis after sinus surgery","volume":"8","author":"Harvey","year":"2018","journal-title":"Int Forum Allergy Rhinol"},{"key":"B102","first-page":"225","article-title":"Expression of glucocorticoid receptor isoforms and associations with serine\/arginine-rich protein 30c and 40 in patients with systemic lupus erythematosus","volume":"33","author":"Guan","year":"2015","journal-title":"Clin Exp Rheumatol."},{"key":"B103","doi-asserted-by":"publisher","first-page":"E158","DOI":"10.1002\/lary.25147","article-title":"Corticosteroid treatment regulates mucosal remodeling in chronic rhinosinusitis with nasal polyps","volume":"125","author":"de Borja Callejas","year":"2015","journal-title":"Laryngoscope."},{"key":"B104","doi-asserted-by":"publisher","first-page":"3346","DOI":"10.3390\/jcm10153346","article-title":"Short term pre-operative oral corticosteroids-tissue remodeling in chronic rhinosinusitis with nasal polyps","volume":"10","author":"Radajewski","year":"2021","journal-title":"J Clin Med."},{"key":"B105","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1080\/1744666X.2016.1220833","article-title":"Chronic rhinosinusitis: the rationale for current treatments","volume":"13","author":"Ghogomu","year":"2017","journal-title":"Expert Rev Clin Immunol"},{"key":"B106","doi-asserted-by":"publisher","first-page":"S9","DOI":"10.1002\/alr.22331","article-title":"Topical corticosteroid irrigations in chronic rhinosinusitis","volume":"9","author":"Grayson","year":"2019","journal-title":"Int Forum Allergy Rhinol"},{"key":"B107","doi-asserted-by":"publisher","first-page":"Cd011992","DOI":"10.1002\/14651858.CD011992.pub2","article-title":"Short-course oral steroids as an adjunct therapy for chronic rhinosinusitis","volume":"4","author":"Head","year":"2016","journal-title":"Cochrane Database Syst Rev."},{"key":"B108","doi-asserted-by":"publisher","first-page":"1455613221088698","DOI":"10.1177\/01455613221088698","article-title":"The effect of EDS-FLU on objective and patient-reported subjective outcomes for patients with chronic rhinosinusitis with nasal polyps","author":"Ow","year":"2022","journal-title":"Ear Nose Throat J."},{"key":"B109","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1177\/1945892418810281","article-title":"NAVIGATE I: randomized, placebo-controlled, double-blind trial of the exhalation delivery system with fluticasone for chronic rhinosinusitis with nasal polyps","volume":"33","author":"Sindwani","year":"2019","journal-title":"Am J Rhinol Allergy"},{"key":"B110","doi-asserted-by":"publisher","first-page":"S4","DOI":"10.1002\/alr.22330","article-title":"Nasal saline irrigation: a clinical update","volume":"9","author":"Succar","year":"2019","journal-title":"Int Forum Allergy Rhinol"},{"key":"B111","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1016\/j.iac.2019.12.014","article-title":"Topical irrigations for chronic rhinosinusitis","volume":"40","author":"Lee","year":"2020","journal-title":"Immunol Allergy Clin North Am."},{"key":"B112","doi-asserted-by":"publisher","first-page":"e0272371","DOI":"10.1371\/journal.pone.0272371","article-title":"Efficacy and safety of traditional Chinese medicine nasal irrigation on chronic rhinosinusitis recovery after endoscopic sinus surgery: a protocol for a systematic review and meta-analysis","volume":"17","author":"Yang","year":"2022","journal-title":"PLoS ONE."},{"key":"B113","doi-asserted-by":"publisher","first-page":"1104","DOI":"10.1002\/alr.21604","article-title":"The effect of nasal irrigation formulation on the antimicrobial activity of nasal secretions","volume":"5","author":"Woods","year":"2015","journal-title":"Int Forum Allergy Rhinol"},{"key":"B114","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1002\/alr.22459","article-title":"Hypertonic saline and seawater solutions damage sinonasal epithelial cell air-liquid interface cultures","volume":"10","author":"Jiao","year":"2020","journal-title":"Int Forum Allergy Rhinol."},{"key":"B115","doi-asserted-by":"publisher","first-page":"1429","DOI":"10.1007\/s00405-014-3233-x","article-title":"The effect of thyme honey nasal spray on chronic rhinosinusitis: a double-blind randomized controlled clinical trial","volume":"272","author":"Hashemian","year":"2015","journal-title":"Eur Arch Oto-Rhino-Laryngol."},{"key":"B116","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1186\/s40463-021-00515-z","article-title":"Patient perspectives on endoscopic sinus surgery for chronic rhinosinusitis","volume":"50","author":"Saydy","year":"2021","journal-title":"J Otolaryngol Head Neck Surg."},{"key":"B117","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1177\/0194599817737977","article-title":"Endoscopic sinus surgery improves sleep quality in chronic rhinosinusitis: a systematic review and meta-analysis","volume":"158","author":"Sukato","year":"2018","journal-title":"Otolaryngol Head Neck Surg."},{"key":"B118","doi-asserted-by":"publisher","first-page":"1056","DOI":"10.1002\/alr.22738","article-title":"Objective sleep measures after endoscopic sinus surgery in patients with chronic rhinosinusitis","volume":"11","author":"Little","year":"2021","journal-title":"Int Forum Allergy Rhinol"},{"key":"B119","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1016\/j.amjoto.2018.07.019","article-title":"Improvement of sinonasal mucociliary function by endoscopic sinus surgery in patients with chronic rhinosinusitis","volume":"39","author":"Naraghi","year":"2018","journal-title":"Am J Otolaryngol"},{"key":"B120","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1007\/s11882-020-00932-6","article-title":"Effect of functional endoscopic sinus surgery on outcomes in chronic rhinosinusitis","volume":"20","author":"Alanin","year":"2020","journal-title":"Curr Allergy Asthma Rep."},{"key":"B121","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1002\/alr.22264","article-title":"Long-term revision rates for endoscopic sinus surgery","volume":"9","author":"Smith","year":"2019","journal-title":"Int Forum Allergy Rhinol."},{"key":"B122","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1002\/lary.26391","article-title":"Prevalence of polyp recurrence after endoscopic sinus surgery for chronic rhinosinusitis with nasal polyposis","volume":"127","author":"DeConde","year":"2017","journal-title":"Laryngoscope"},{"key":"B123","doi-asserted-by":"publisher","first-page":"1047","DOI":"10.1002\/alr.22146","article-title":"Revision endoscopic sinus surgery rates by chronic rhinosinusitis subtype","volume":"8","author":"Miglani","year":"2018","journal-title":"Int Forum Allergy Rhinol."},{"key":"B124","doi-asserted-by":"publisher","first-page":"664","DOI":"10.4168\/aair.2019.11.5.664","article-title":"Immunological characteristics in refractory chronic rhinosinusitis with nasal polyps undergoing revision surgeries","volume":"11","author":"Ryu","year":"2019","journal-title":"Allergy Asthma Immunol Res"},{"key":"B125","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1002\/alr.22487","article-title":"Revision surgery rates in chronic rhinosinusitis with nasal polyps: meta-analysis of risk factors","volume":"10","author":"Loftus","year":"2020","journal-title":"Int Forum Allergy Rhinol"},{"key":"B126","doi-asserted-by":"publisher","first-page":"1197","DOI":"10.1002\/alr.22779","article-title":"Asthma increases long-term revision rates of endoscopic sinus surgery in chronic rhinosinusitis with and without nasal polyposis","volume":"11","author":"Gill","year":"2021","journal-title":"Int Forum Allergy Rhinol"},{"key":"B127","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1016\/j.anorl.2020.12.002","article-title":"Biotherapy and treatment of adult primary chronic rhinosinusitis with nasal polyps: cellular and molecular bases","volume":"138","author":"Bartier","year":"2021","journal-title":"Eur Ann Otorhinolaryngol Head Neck Dis."},{"key":"B128","doi-asserted-by":"publisher","first-page":"1141","DOI":"10.1016\/s2213-2600(21)00097-7","article-title":"Mepolizumab for chronic rhinosinusitis with nasal polyps (SYNAPSE): a randomised, double-blind, placebo-controlled, phase 3 trial","volume":"9","author":"Han","year":"2021","journal-title":"Lancet Respir Med."},{"key":"B129","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1007\/s11882-014-0435-7","article-title":"Cytokine profiles in allergic rhinitis","volume":"14","author":"Scadding","year":"2014","journal-title":"Curr Allergy Asthma Rep."},{"key":"B130","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1007\/s40265-022-01679-2","article-title":"Tezepelumab: first approval","volume":"82","author":"Hoy","year":"2022","journal-title":"Drugs."},{"key":"B131","doi-asserted-by":"publisher","first-page":"1299","DOI":"10.1016\/S2213-2600(21)00226-5","article-title":"Effect of tezepelumab on airway inflammatory cells, remodelling, and hyperresponsiveness in patients with moderate-to-severe uncontrolled asthma (CASCADE): a double-blind, randomised, placebo-controlled, phase 2 trial","volume":"9","author":"Diver","year":"2021","journal-title":"Lancet Respir Med."},{"key":"B132","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1177\/1945892420961969","article-title":"Dupilumab as add-on therapy for chronic rhinosinusitis with nasal polyposis in aspirin exacerbated respiratory disease","volume":"35","author":"Mustafa","year":"2021","journal-title":"Am J Rhinol Allergy"},{"key":"B133","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1001\/jama.2015.19330","article-title":"Effect of subcutaneous dupilumab on nasal polyp burden in patients with chronic sinusitis and nasal polyposis: a randomized clinical trial","volume":"315","author":"Bachert","year":"2016","journal-title":"JAMA."},{"key":"B134","doi-asserted-by":"publisher","first-page":"456","DOI":"10.1056\/NEJMcp1412282","article-title":"Clinical practice. Allergic rhinitis","volume":"372","author":"Wheatley","year":"2015","journal-title":"N Engl J Med."},{"key":"B135","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1177\/19458924211030486","article-title":"Defining the efficacy of omalizumab in nasal polyposis: a POLYP 1 and POLYP 2 subgroup analysis","volume":"36","author":"Damask","year":"2022","journal-title":"Am J Rhinol Allergy"},{"key":"B136","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1016\/j.jaci.2020.05.032","article-title":"Efficacy and safety of omalizumab in nasal polyposis: 2 randomized phase 3 trials","volume":"146","author":"Gevaert","year":"2020","journal-title":"J Allergy Clin Immunol."},{"key":"B137","doi-asserted-by":"publisher","first-page":"957","DOI":"10.1016\/j.jaci.2021.07.045","article-title":"Long-term efficacy and safety of omalizumab for nasal polyposis in an open-label extension study","volume":"149","author":"Gevaert","year":"2022","journal-title":"J Allergy Clin Immuno."},{"key":"B138","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1111\/j.1398-9995.2011.02735.x","article-title":"Anti-IL-33 antibody has a therapeutic effect in a murine model of allergic rhinitis","volume":"67","author":"Kim","year":"2012","journal-title":"Allergy."},{"key":"B139","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1007\/s12016-019-08734-z","article-title":"Therapeutic antibodies for nasal polyposis treatment: where are we headed?","volume":"59","author":"Agarwal","year":"2020","journal-title":"Clin Rev Allergy Immunol."}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2023.1139240\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,17]],"date-time":"2023-04-17T05:34:08Z","timestamp":1681709648000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2023.1139240\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,17]]},"references-count":139,"alternative-id":["10.3389\/fmed.2023.1139240"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2023.1139240","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,17]]},"article-number":"1139240"}}