{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T18:25:42Z","timestamp":1792520742596,"version":"4.5.0"},"reference-count":45,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2024,9,10]],"date-time":"2024-09-10T00:00:00Z","timestamp":1725926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Animalfree Research, Bern, Switzerland"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The integrity of the blood\u2013labyrinth barrier (BLB) is essential for inner ear homeostasis, regulating the ionic composition of endolymph and perilymph and preventing harmful substance entry. Endothelial hyperpermeability, central in inflammatory and immune responses, is managed through complex intercellular communication and molecular signaling pathways. Recent studies link BLB permeability dysregulation to auditory pathologies like acoustic trauma, autoimmune inner ear diseases, and presbycusis. Polymorphonuclear granulocytes (PMNs), or neutrophils, significantly modulate vascular permeability, impacting endothelial barrier properties. Neutrophil extracellular traps (NETs) are involved in diseases with autoimmune and autoinflammatory bases. The present study evaluated the impact of NETs on a BLB cellular model using a Transwell\u00ae setup. Our findings revealed a concentration-dependent impact of NETs on human inner ear-derived endothelial cells. In particular, endothelial permeability markers increased, as indicated by reduced transepithelial electrical resistance, enhanced dextran permeability, and downregulated junctional gene expression (ZO1, OCL, and CDH5). Changes in cytoskeletal architecture were also observed. These preliminary results pave the way for further research into the potential involvement of NETs in BLB impairment and implications for auditory disorders.<\/jats:p>","DOI":"10.3390\/ijms25189766","type":"journal-article","created":{"date-parts":[[2024,9,10]],"date-time":"2024-09-10T03:16:51Z","timestamp":1725938211000},"page":"9766","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Neutrophil Extracellular Traps Affect Human Inner Ear Vascular Permeability"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3761-7253","authenticated-orcid":false,"given":"Marijana","family":"Sekulic","sequence":"first","affiliation":[{"name":"Department of Biomedicine, University Hospital Basel, University of Basel, 4031 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2216-9539","authenticated-orcid":false,"given":"Stavros","family":"Giaglis","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, University Hospital Basel, University of Basel, 4031 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Chatelain","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, University Hospital Basel, University of Basel, 4031 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Bodmer","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, University Hospital Basel, University of Basel, 4031 Basel, Switzerland"},{"name":"Clinic for Otorhinolaryngology, University Hospital Basel, University of Basel, 4031 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0741-9774","authenticated-orcid":false,"given":"Vesna","family":"Petkovic","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, University Hospital Basel, University of Basel, 4031 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e19","DOI":"10.1017\/S1462399409001112","article-title":"Molecular mechanisms of endothelial hyperpermeability: Implications in inflammation","volume":"11","author":"Kumar","year":"2009","journal-title":"Expert Rev. Mol. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1177\/000348948109000208","article-title":"Nature of blood-labyrinth barrier in experimental conditions","volume":"90","author":"Juhn","year":"1981","journal-title":"Ann. Otol. Rhinol. Laryngol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/S0378-5955(98)00214-7","article-title":"Development of blood-labyrinth barrier in the semicircular canal ampulla of the rat","volume":"129","author":"Suzuki","year":"1999","journal-title":"Hear. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/S0196-0709(82)80016-1","article-title":"Transport characteristics of the blood--perilymph barrier","volume":"3","author":"Juhn","year":"1982","journal-title":"Am. J. Otolaryngol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.heares.2011.08.006","article-title":"Physiopathology of the cochlear microcirculation","volume":"282","author":"Shi","year":"2011","journal-title":"Hear. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1007\/s10162-012-0365-9","article-title":"Endothelial cell, pericyte, and perivascular resident macrophage-type melanocyte interactions regulate cochlear intrastrial fluid-blood barrier permeability","volume":"14","author":"Neng","year":"2013","journal-title":"J. Assoc. Res. Otolaryngol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Yang, Y., Dai, M., Wilson, T.M., Omelchenko, I., Klimek, J.E., Wilmarth, P.A., David, L.L., Nuttall, A.L., Gillespie, P.G., and Shi, X. (2011). Na+\/K+-ATPase \u03b11 identified as an abundant protein in the blood-labyrinth barrier that plays an essential role in the barrier integrity. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0016547"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1083\/jcb.135.2.497","article-title":"Polymorphonuclear leukocyte adhesion triggers the disorganization of endothelial cell-to-cell adherens junctions","volume":"135","author":"Zanetti","year":"1996","journal-title":"J. Cell Biol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Urban, C.F., Ermert, D., Schmid, M., Abu-Abed, U., Goosmann, C., Nacken, W., Brinkmann, V., Jungblut, P.R., and Zychlinsky, A. (2009). Neutrophil extracellular traps contain calprotectin, a cytosolic protein complex involved in host defense against Candida albicans. PLoS Pathog., 5.","DOI":"10.1371\/journal.ppat.1000639"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"R122","DOI":"10.1186\/ar4579","article-title":"Enhanced neutrophil extracellular trap generation in rheumatoid arthritis: Analysis of underlying signal transduction pathways and potential diagnostic utility","volume":"16","author":"Giaglis","year":"2014","journal-title":"Arthritis Res. Ther."},{"key":"ref_11","first-page":"w14352","article-title":"Neutrophil extracellular traps in health and disease","volume":"146","author":"Hasler","year":"2016","journal-title":"Swiss Med. Wkly."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Giaglis, S., Hahn, S., and Hasler, P. (2016). The NET Outcome: Are Neutrophil Extracellular Traps of Any Relevance to the Pathophysiology of Autoimmune Disorders in Childhood?. Front. Pediatr., 4.","DOI":"10.3389\/fped.2016.00097"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1007\/s12016-020-08804-7","article-title":"A Review of Neutrophil Extracellular Traps (NETs) in Disease: Potential Anti-NETs Therapeutics","volume":"61","author":"Mutua","year":"2021","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"27201","DOI":"10.1074\/jbc.271.44.27201","article-title":"Endothelial cell death induced by tumor necrosis factor-alpha is inhibited by the Bcl-2 family member, A1","volume":"271","author":"Karsan","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"H768","DOI":"10.1152\/ajpheart.00779.2014","article-title":"Mitochondrial N-formyl peptides induce cardiovascular collapse and sepsis-like syndrome","volume":"308","author":"Wenceslau","year":"2015","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1903","DOI":"10.3174\/ajnr.A4822","article-title":"Blood-Labyrinth Barrier Permeability in Meni\u00e8re Disease and Idiopathic Sudden Sensorineural Hearing Loss: Findings on Delayed Postcontrast 3D-FLAIR MRI","volume":"37","author":"Pakdaman","year":"2016","journal-title":"AJNR Am. J. Neuroradiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e12506","DOI":"10.1111\/micc.12506","article-title":"Sphingosine-1-phosphate protects against brain microvascular endothelial junctional protein disorganization and barrier dysfunction caused by alcohol","volume":"26","author":"Alves","year":"2019","journal-title":"Microcirculation"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e978720","DOI":"10.4161\/21688370.2014.978720","article-title":"Blood cells and endothelial barrier function","volume":"3","author":"Rodrigues","year":"2015","journal-title":"Tissue Barriers"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1243370","DOI":"10.3389\/fnmol.2023.1243370","article-title":"Human blood-labyrinth barrier model to study the effects of cytokines and inflammation","volume":"16","author":"Sekulic","year":"2023","journal-title":"Front. Mol. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/1755-1536-6-11","article-title":"Neutrophil roles in left ventricular remodeling following myocardial infarction","volume":"6","author":"Ma","year":"2013","journal-title":"Fibrogenesis Tissue Repair"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e12352","DOI":"10.1111\/micc.12352","article-title":"Neutrophil-mediated vascular barrier injury: Role of neutrophil extracellular traps","volume":"24","author":"Meegan","year":"2017","journal-title":"Microcirculation"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/S0891-5849(02)00823-7","article-title":"Mediators and regulation of neutrophil accumulation in inflammatory responses in lung: Insights from the IgG immune complex model","volume":"33","author":"Guo","year":"2002","journal-title":"Free Radic. Biol. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1146\/annurev.pathol.1.110304.100155","article-title":"Regulation of lung inflammation in the model of IgG immune-complex injury","volume":"1","author":"Gao","year":"2006","journal-title":"Annu. Rev. Pathol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Zhou, P., Lu, S., Luo, Y., Wang, S., Yang, K., Zhai, Y., Sun, G., and Sun, X. (2017). Attenuation of TNF-\u03b1-Induced Inflammatory Injury in Endothelial Cells by Ginsenoside Rb1 via Inhibiting NF-\u03baB, JNK and p38 Signaling Pathways. Front. Pharmacol., 8.","DOI":"10.3389\/fphar.2017.00464"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1006\/bbrc.2002.6487","article-title":"Cytotoxicity of IFN-\u03b3 and TNF-\u03b1 for Vascular Endothelial Cell Is Mediated by Nitric Oxide","volume":"291","author":"Yamaoka","year":"2002","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1038\/ki.1997.170","article-title":"Effects of TNF alpha on verocytotoxin cytotoxicity in purified human glomerular microvascular endothelial cells","volume":"51","author":"Vermeer","year":"1997","journal-title":"Kidney Int."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Hudock, K.M., Collins, M.S., Imbrogno, M.A., Kramer, E.L., Brewington, J.J., Ziady, A., Zhang, N., Snowball, J., Xu, Y., and Carey, B.C. (2023). Alpha-1 antitrypsin limits neutrophil extracellular trap disruption of airway epithelial barrier function. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1023553"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1159\/000460293","article-title":"Neutrophil Extracellular Traps Stimulate Proinflammatory Responses in Human Airway Epithelial Cells","volume":"9","author":"Sabbione","year":"2017","journal-title":"J. Innate Immun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1093\/ibd\/izac256","article-title":"Histones of Neutrophil Extracellular Traps Directly Disrupt the Permeability and Integrity of the Intestinal Epithelial Barrier","volume":"29","author":"Lai","year":"2023","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"20587392211062386","DOI":"10.1177\/20587392211062386","article-title":"Neutrophil extracellular traps are associated with altered human pulmonary artery endothelial barrier function","volume":"19","author":"Mori","year":"2021","journal-title":"Eur. J. Inflamm."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1016\/j.freeradbiomed.2011.11.002","article-title":"Role of reactive oxygen and nitrogen species in the vascular responses to inflammation","volume":"52","author":"Kvietys","year":"2012","journal-title":"Free Radic. Biol. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1089\/ars.2012.5149","article-title":"Reactive oxygen species in inflammation and tissue injury","volume":"20","author":"Rizwan","year":"2014","journal-title":"Antioxi. Redox Signal."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1161\/CIRCRESAHA.112.274548","article-title":"S-Nitrosation of \u03b2-catenin and p120 catenin: A novel regulatory mechanism in endothelial hyperpermeability","volume":"111","author":"Zamorano","year":"2012","journal-title":"Circ. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2522","DOI":"10.2741\/3395","article-title":"Endothelial signaling in paracellular and transcellular leukocyte transmigration","volume":"14","author":"Wittchen","year":"2009","journal-title":"Front. Biosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1038\/nri3908","article-title":"How leukocytes cross the vascular endothelium","volume":"15","author":"Vestweber","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1161\/ATVBAHA.117.309002","article-title":"Neutrophil Extracellular Traps Drive Endothelial-to-Mesenchymal Transition","volume":"37","author":"Pieterse","year":"2017","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2661","DOI":"10.1172\/JCI61303","article-title":"Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury","volume":"122","author":"Caudrillier","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1498","DOI":"10.1016\/j.bbrc.2018.07.069","article-title":"Citrullinated histone 3 causes endothelial barrier dysfunction","volume":"503","author":"Meegan","year":"2018","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"14002","DOI":"10.1074\/jbc.M300351200","article-title":"Identification of proteases involved in the proteolysis of vascular endothelium cadherin during neutrophil transmigration","volume":"278","author":"Hermant","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_40","first-page":"H385","article-title":"Neutrophil elastase promotes lung microvascular injury and proteolysis of endothelial cadherins","volume":"275","author":"Carden","year":"1998","journal-title":"Am. J. Physiol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Ma, Y., Yang, X., Chatterjee, V., Meegan, J.E., Beard, R.S., and Yuan, S.Y. (2019). Role of Neutrophil Extracellular Traps and Vesicles in Regulating Vascular Endothelial Permeability. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.01037"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1111\/joim.12016","article-title":"Endothelial cell metabolism and tumour angiogenesis: Glucose and glutamine as essential fuels and lactate as the driving force","volume":"273","author":"Polet","year":"2013","journal-title":"J. Intern. Med."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Klopf, J., Brostjan, C., Eilenberg, W., and Neumayer, C. (2021). Neutrophil Extracellular Traps and Their Implications in Cardiovascular and Inflammatory Disease. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22020559"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1038\/nm.4294","article-title":"An emerging role for neutrophil extracellular traps in noninfectious disease","volume":"23","author":"Jorch","year":"2017","journal-title":"Nat. Med."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Zou, J., Zhao, Z., Song, X., Zhang, G., Li, H., Zhang, Q., and Pyykk\u00f6, I. (2022). Elevated G-CSF, IL8, and HGF in patients with definite Meniere\u2019s disease may indicate the role of NET formation in triggering autoimmunity and autoinflammation. Sci. Rep., 12.","DOI":"10.1038\/s41598-022-20774-8"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/18\/9766\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:52:36Z","timestamp":1760111556000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/18\/9766"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,10]]},"references-count":45,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2024,9]]}},"alternative-id":["ijms25189766"],"URL":"https:\/\/doi.org\/10.3390\/ijms25189766","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,10]]}}}