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      Human blood-labyrinth barrier model to study the effects of cytokines and inflammation


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          Hearing loss is one of the 10 leading causes of disability worldwide. No drug therapies are currently available to protect or restore hearing. Inner ear auditory hair cells and the blood-labyrinth barrier (BLB) are critical for normal hearing, and the BLB between the systemic circulation and stria vascularis is crucial for maintaining cochlear and vestibular homeostasis. BLB defects are associated with inner ear diseases that lead to hearing loss, including vascular malformations, inflammation, and Meniere’s disease (MD). Antibodies against proteins in the inner ear and cytokines in the cochlea, including IL-1α, TNF-α, and NF-kβ, are detected in the blood of more than half of MD patients. There is also emerging evidence of inner ear inflammation in some diseases, including MD, progressive sensorineural hearing loss, otosclerosis, and sudden deafness. Here, we examined the effects of TNF-α, IL6, and LPS on human stria vascularis-derived primary endothelial cells cultured together with pericytes in a Transwell system. By measuring trans-endothelial electrical resistance, we found that TNF-α causes the most significant disruption of the endothelial barrier. IL6 had a moderate influence on the barrier, whereas LPS had a minimal impact on barrier integrity. The prominent effect of TNF-α on the barrier was confirmed in the expression of the major junctional genes responsible for forming the tight endothelial monolayer, the decreased expression of ZO1 and OCL. We further tested permeability using 2 μg of daptomycin (1,619 Da), which does not pass the BLB under normal conditions, by measuring its passage through the barrier by HPLC. Treatment with TNF-α resulted in higher permeability in treated samples compared to controls. LPS-treated cells behaved similarly to the untreated cells and did not show differences in permeability compared to control. The endothelial damage caused by TNF-α was confirmed by decreased expression of an essential endothelial proteoglycan, syndecan1. These results allowed us to create an inflammatory environment model that increased BLB permeability in culture and mimicked an inflammatory state within the stria vascularis.

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          Most cited references42

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          TNF-mediated inflammatory disease.

          JR Bradley (2008)
          TNF was originally described as a circulating factor that can cause necrosis of tumours, but has since been identified as a key regulator of the inflammatory response. This review describes the known signalling pathways and cell biological effects of TNF, and our understanding of the role of TNF in human disease. TNF interacts with two different receptors, designated TNFR1 and TNFR2, which are differentially expressed on cells and tissues and initiate both distinct and overlapping signal transduction pathways. These diverse signalling cascades lead to a range of cellular responses, which include cell death, survival, differentiation, proliferation and migration. Vascular endothelial cells respond to TNF by undergoing a number of pro-inflammatory changes, which increase leukocyte adhesion, transendothelial migration and vascular leak and promote thrombosis. The central role of TNF in inflammation has been demonstrated by the ability of agents that block the action of TNF to treat a range of inflammatory conditions, including rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease and psoriasis. The increased incidence of infection in patients receiving anti-TNF treatment has highlighted the physiological role of TNF in infectious diseases. 2007 Pathological Society of Great Britain and Ireland
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            Proinflammatory cytokines expression in noise-induced damaged cochlea.

            Recent studies have showed that inflammatory responses occur in inner ear under various damaging conditions including noise-overstimulation. We evaluated the time-dependent expression of proinflammatory cytokines in noise-exposed rat cochlea. Among several detected cytokines, real-time RT-PCR showed that interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) were significantly induced 3 hr after noise exposure, and quickly downregulated to the basal level. Tumor necrosis factor-alpha (TNF-alpha) was also slightly upregulated immediately after noise exposure. Immunohistochemical analysis showed that IL-6 expression was distinctively induced within the lateral side of the spiral ligament. Sequential expression analysis showed that IL-6 immunoreactivity was initially found in the cytoplasm of lateral wall cells, including Type IV and III fibrocytes, and expanded broader throughout the lateral wall, finally to the stria vascularis. Because of the negative Iba-1 staining, IL-6 expression in the early-phase was not due to macrophage or microglia activation. IL-6 was also detected in spiral ganglion neurons at 12 and 24 hr after noise exposure. Our data demonstrates the production of proinflammatory cytokines, including TNF-alpha, IL-1beta, and IL-6, in early phase of noise overstimulated cochlea. IL-6 expression was observed in the spiral ligament, stria vascularis, and spiral ganglion neurons. These cytokines, produced by the cochlear structure itself in response to noise exposure, may initiate an inflammatory response and have some role in the mechanism of noise-induced cochlear damage. Copyright 2006 Wiley-Liss, Inc.
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              Pathophysiology of Meniere's syndrome: are symptoms caused by endolymphatic hydrops?

              The association of Meniere's syndrome with endolymphatic hydrops has led to the formation of a central hypothesis: many possible etiologic factors lead to hydrops, and hydrops in turn generates the symptoms. However, this hypothesis of hydrops as being the final common pathway has not been proven conclusively. To examine human temporal bones with respect to the role of hydrops in causing symptoms in Meniere's syndrome. If the central hypothesis were true, every case of Meniere's syndrome should have hydrops and every case of hydrops should show the typical symptoms. Review of archival temporal bone cases with a clinical diagnosis of Meniere's syndrome (28 cases) or a histopathologic diagnosis of hydrops (79 cases). All 28 cases with classical symptoms of Meniere's syndrome showed hydrops in at least one ear. However, the reverse was not true. There were 9 cases with idiopathic hydrops and 10 cases with secondary hydrops, but the patients did not exhibit the classic symptoms of Meniere's syndrome. A review of the literature revealed cases with asymptomatic hydrops (similar to the current study), as well as cases where symptoms of Meniere's syndrome existed during life but no hydrops was observed on histology. We also review recent experimental data where obstruction of the endolymphatic duct in guinea pigs resulted in cytochemical abnormalities within fibrocytes of the spiral ligament before development of hydrops. This result is consistent with the hypothesis that hydrops resulted from disordered fluid homeostasis caused by disruption of regulatory elements within the spiral ligament. Endolymphatic hydrops should be considered as a histologic marker for Meniere's syndrome rather than being directly responsible for its symptoms.

                Author and article information

                Front Mol Neurosci
                Front Mol Neurosci
                Front. Mol. Neurosci.
                Frontiers in Molecular Neuroscience
                Frontiers Media S.A.
                21 September 2023
                : 16
                : 1243370
                [1] 1Department of Biomedicine, University Hospital Basel, University of Basel , Basel, Switzerland
                [2] 2University Hospital Basel, Clinic for Otorhinolaryngology , Basel, Switzerland
                Author notes

                Edited by: Jennie Cederholm, University of New South Wales, Australia

                Reviewed by: Jose Antonio Lopez-Escamez, University of Sydney, Australia; Jing Zou, Second Military Medical University, China

                *Correspondence: Marijana Sekulic, marijana.sekulic@ 123456unibas.ch

                These authors have contributed equally to this work

                Copyright © 2023 Sekulic, Puche, Bodmer and Petkovic.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                : 07 July 2023
                : 31 August 2023
                Page count
                Figures: 5, Tables: 0, Equations: 0, References: 42, Pages: 10, Words: 6828
                Molecular Neuroscience
                Original Research
                Custom metadata
                Molecular Signalling and Pathways

                blood-labyrinth barrier,cytokines,disease model,hearing loss,inflammation
                blood-labyrinth barrier, cytokines, disease model, hearing loss, inflammation


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