Mechanism Of Sensorineural Hearing Loss Research Articles

Deferoxamine protects cochlear hair cells and hair cell-like HEI-OC1 cells against tert-butyl hydroperoxide-induced ototoxicity

Oxidative stress is the common mechanism of sensorineural hearing loss (SNHL) caused by many factors, such as noise, drugs and ageing. Here, we used tert-butyl hydroperoxide (t-BHP) to cause oxidative stress damage in HEI-OC1 cells and in an in vitro cochlear explant model. We observed lipid peroxidation, iron accumulation, mitochondrial shrinkage and vanishing of mitochondrial cristae, which caused hair cell ferroptosis, after t-BHP exposure. Moreover, the number of TUNEL-positive cells in cochlear explants and HEI-OC1 cells increased significantly, suggesting that t-BHP caused the apoptosis of hair cells. Administration of deferoxamine (DFOM) significantly attenuated t-BHP-induced hair cell loss and disordered hair cell arrangement in cochlear explants as well as HEI-OC1 cell death, including via apoptosis and ferroptosis. Mechanistically, we found that DFOM treatment reduced t-BHP-induced lipid peroxidation, iron accumulation and mitochondrial pathological changes in hair cells, consequently mitigating apoptosis and ferroptosis. Moreover, DFOM treatment alleviated GSH depletion caused by t-BHP and activated the Nrf2 signalling pathway to exert a protective effect. Furthermore, we confirmed that the protective effect of DFOM mainly depended on its ability to chelate iron by constructing Fth1 knockout (KO), TfR1 KO and Nrf2 KO HEI-OC1 cell lines using CRISPR/Cas9 technology and a Flag-Fth1 (overexpression) HEI-OC1 cell line using the FlpIn™ System. Our findings suggest that DFOM is a potential drug for SNHL treatment due to its ability to inhibit apoptosis and ferroptosis by chelating iron and scavenging reactive oxygen species (ROS).

Zebrafish models of sensorineural hearing loss

Sensorineural hearing loss negatively impacts over 450 million people worldwide. While we know that insults such as ototoxic drugs and noise damage sensory hair cells, our understanding of damage mechanisms is incomplete. Zebrafish are an exciting vertebrate model for research on fundamental mechanisms of hair cell damage. In addition to the inner ear, zebrafish have a lateral line system containing clusters of externally located hair cells. These hair cells are homologous to vertebrate inner ear hair cells and respond similarly to ototoxic damage. Our lab uses the lateral line system to determine the ototoxic potential of COVID-19 therapies; with over 900 medications currently in clinical trials, it is highly likely that a subset of those medications causes mild hearing loss that is not detected in clinical settings. In addition, while ototoxicity is a significant concern for patients exposed to these medications, acoustic damage and age-related hearing loss are far more prevalent in the general population. Our lab developed a zebrafish model of acoustic trauma and showed that noise exposure causes synaptic damage and hair cell loss in the larval lateral line analogous to the damage observed in the mammalian cochlea. Finally, we show that aged adult zebrafish lose both lateral line and inner ear hair cells similar to hair cell loss seen in aging mammals. Collectively, our research demonstrates that zebrafish are a tractable model to understand mechanisms of sensorineural hearing loss and to test therapeutic strategies.

Modern technologies for the diagnostics and treatment of hearing diseases (Lecture for pharmacists - in the field of training 38.03.07 “Commodity science”)

The lecture describes the morphofunctional organization of the sound-conducting and sound-receiving structures of the auditory analyzer. The most common types of pathology that lead to impaired functions of the hearing organ are described. Causes and mechanisms of development of two main types of hearing impairment conductive and sensorineural hearing loss are highlighted. Modern hardware complexes and operational technologies are shown, which are used for the diagnosis and treatment of conductive hearing disorders. Causes and mechanisms of sensorineural hearing loss are highlighted. Microelectronic devices (cochlear implants) and the technology of their transplantation into the affected hearing organ are described. The characteristics of hearing aids, which are most often recommended by experts to patients of various ages with hearing impairment, are given.

Generation of innervated cochlear organoid recapitulates early development of auditory unit.

Functional cochlear hair cells (HCs) innervated by spiral ganglion neurons (SGNs) are essential for hearing, whereas robust models that recapitulate the peripheral auditory circuity are still lacking. Here, we developed cochlear organoids with functional peripheral auditory circuity in a staging three-dimensional (3D) co-culture system by initially reprogramming cochlear progenitor cells (CPCs) with increased proliferative potency that could be long-term expanded, then stepwise inducing the differentiation of cochlear HCs, as well as the outgrowth of neurites from SGNs. The function of HCs and synapses within organoids was confirmed by a series of morphological and electrophysiological evaluations. Single-cell mRNA sequencing revealed the differentiation trajectories of CPCs toward the major cochlear cell types and the dynamic gene expression during organoid HC development, which resembled the pattern of native HCs. We established the cochlear organoids with functional synapses for the first time, which provides a platform for deciphering the mechanisms of sensorineural hearing loss.

Патогенетичні механізми сенсоневральної втрати слуху в пацієнтів з COVID-19 і методи їх корекції

У статті описані основні патогенетичні механізми розвитку гострої сенсоневральної втрати слуху, у тому числі інфекційного генезу. Розглянуто можливі чинники й механізми розвитку сенсоневральної втрати слуху на фоні коронавірусної інфекції, спричиненої вірусом SARS-CoV-2. Описані випадки зниження слуху в пацієнтів з COVID-19. Наведений патогенетично обґрунтований терапевтичний підхід у лікуванні таких пацієнтів, що заснований на оптимізації ацетилхолінової нейромедіації в структурах головного мозку, які беруть участь у проведенні й сприйнятті слухового імпульсу.

Sensorineural hearing loss as a predictor of endothelial dysfunction in some non-communicable diseases in the working population (a review of interdisciplinary studies)

Interdisciplinary publications suggesting an etiopathogenetic relationship between sensorineural hearing loss and some chronic non-communicable diseases were reviewed. A substantial amount of data on atherogenesis, thrombosis and immunological processes affecting the blood circulation of inner ear receptor cells has so far been accumulated. Various reasons for sensorineural hearing loss have been studied, such as changes in the rheological properties of blood; arteriole hypertonicity; precapillar sphincter dysfunction; impaired lipid metabolism leading to the lack of tissue oxygenation and dystrophy and necrosis of the organ of Corti. The definition of endothelial dysfunction has been given. The role of vasomotor, thrombophilic, adhesive and angiogenic forms of endothelial dysfunction in the development and progression of sensorineural hearing loss under the influence of harmful work-related factors, with arterial hypertension, coronary heart disease, diabetes mellitus with the most common and aggressive disorders of the microvasculature has been determined. A clear relationship between the development of sensorineural hearing loss in diabetic microangiopathy has been established. Historical data on the study of the mechanisms of sensorineural hearing loss were analyzed. The aim of this article was to conduct a literature review of interdisciplinary publications with a particular focus on the role of sensorineural hearing loss in the working population in predicting endothelial dysfunction in some chronic non-communicable diseases. The novelty of this article consists in the consideration of occupational and population risk factors for chronic non-communicable diseases in the form of their cascade, which also leads to sensorineural hearing loss.

Relationship between Metabolomics Profile of Perilymph in Cochlear-Implanted Patients and Duration of Hearing Loss.

Perilymph metabolomic analysis is an emerging innovative strategy to improve our knowledge of physiopathology in sensorineural hearing loss. This study aims to develop a metabolomic profile of human perilymph with which to evaluate the relationship between metabolome and the duration of hearing loss. Inclusion criteria were eligibility for cochlear implantation and easy access to the round window during surgery; patients with residual acoustic hearing in the ear to be implanted were excluded. Human perilymph was sampled from 19 subjects during cochlear implantation surgery. The perilymph analysis was performed by Liquid Chromatography−High-Resolution Mass and data were analyzed by supervised multivariate analysis based on Partial Least-Squares Discriminant Analysis and univariate analysis. Samples were grouped according to their median duration of hearing loss. We included the age of patients as a covariate in our models. Statistical analysis and pathways evaluation were performed using Metaboanalyst. Nineteen samples of human perilymph were analyzed, and a total of 106 different metabolites were identified. Metabolomic profiles were significantly different for subjects with ≤12 or >12 years of hearing loss, highlighting the following discriminant compounds: N-acetylneuraminate, glutaric acid, cystine, 2-methylpropanoate, butanoate and xanthine. As expected, the age of patients was also one of the main discriminant parameters. Metabolic signatures were observed for duration of hearing loss. These findings are promising steps towards illuminating the pathophysiological pathways associated with etiologies of sensorineural hearing loss, and hold open the possibilities of further explorations into the mechanisms of sensorineural hearing loss using metabolomic analysis.

Pathophysiology of sensorineural hearing loss in jugular foramen paraganglioma.

Pathologic involvement of the inferior cochlear vein is a mechanism of sensorineural hearing loss in patients with jugular foramen paraganglioma. Retrospective case-control study. The presenting audiograms, magnetic resonance imaging, and computed tomography were reviewed in 46 subjects with jugular foramen paragangliomas. Four-frequency bone conduction average was compared between the tumor and nontumor ears in each subject to establish the presence of sensorineural hearing loss. Imaging findings for each subject were recorded. Univariate and multivariate statistical analyses were performed to determine which radiographic features were associated with sensorineural hearing loss. Hearing data were analyzed as a continuous variable and as a categorical variable. Twenty subjects (43.4%) had a bone-conduction pure-tone asymmetry of greater than 15 dB. Inferior cochlear vein involvement was identified in 19 of the 20 (95%) subjects with sensorineural hearing loss. Inferior cochlear vein involvement was found to be a statistically significant predictor of sensorineural hearing loss using univariate and multivariate analyses. Other imaging findings that were statistically significant predictors of sensorineural hearing loss include Glasscock-Jackson stage, Fisch-Mattox stage, hypoglossal canal involvement, jugulo-carotid spin erosion, and petrous carotid canal erosion. Involvement of the inferior cochlear vein appears to be a plausible mechanism for sensorineural hearing loss in patients with jugular foramen paraganglioma. 4 Laryngoscope, 129:67-75, 2019.

Temporal Bone Histopathology of X-linked Inherited Alport Syndrome.

ObjectiveTo describe the histopathologic findings within the human cochlea in X‐linked Alport syndrome.Study DesignHistopathologic analysis of cellular elements within the human cochlea by light microscopy.Materials and MethodsA right and a left cochleae of a man with genetically confirmed X‐linked Alport syndrome was studied post‐mortem. The temporal bones underwent standard processing for histologic examination. The slides were examined by light microscopy. Graphic reconstruction of the cochlea was performed to quantify hair cells, pathologic changes of the stria vascularis, and loss of cochlear neuronal cells.ResultsThere was severe loss of inner hair cells and all three rows of outer hair cells in the apical two turns of the cochlea. The stria vascularis and spiral ligament showed areas of marked loss which became more prominent from base to apex in each ear. The spiral ganglion cell count in the Rosenthal's canal exhibited loss of 20% to 45% compared to matched historical controls. There was a zone of separation between the organ of Corti and the basilar membrane extending along the basal surface of Deiters cells, Hensen cells, Claudius cells and external sulcus cells. The tunnel of Corti and the space of Nuel were filled with cellular elements along the cochlea.ConclusionThe histopathologic findings of cochlear involvement in Alport's syndrome are basement membrane separation from the cells of the organ of Corti, outer and inner hair cell loss, and cellular infilling of the tunnel and extracellular spaces of the organ of Corti. These observations contribute to our understanding of the mechanism of sensorineural hearing loss in these patients.Level of Evidence

Localization of prestin and expression in the early period after radiation in mice

This study aimed to examine expression and microstructural distribution of prestin in outer hair cells, and the effect of dose and time of radiation on prestin expression in the BALB/c mouse. We also investigated the molecular biological characteristics of prestin and possible mechanisms of sensorineural hearing loss caused by radiation. Seventy 4-week-old mice were randomly divided into four groups, including one control group and three experimental groups. Each experimental group was randomly divided into two groups, which were killed to collect specimens of the cochlea on the 3rd and 7th days after exposure to different doses of 8, 12, and 16 Gy radiation. These cochleas were embedded in paraffin, and then cut into sections. The sections were immunostained with anti-prestin antibodies. The distribution of prestin was observed under optical microscopy and the density of prestin-positive expression was quantitatively calculated by Image-Pro Plus. Prestin had high expression in the lateral membrane and low expression in the cytoplasm of outer hair cells above the nucleus. The density of prestin protein expression of the basal turn was not significantly different after exposure to the different doses of radiation compared with the control group, but up-regulation occurred after radiation in the apex turn. We conclude that prestin protein is mainly expressed in the lateral membrane above the nucleus. Prestin protein may be responsible for the mechanism of injury to the inner ear caused by radiation.

In Response to Letter to the Editor

To the Editor Thank you for your letter and comments. We agree there may be multiple mechanisms of sensorineural hearing loss in otosclerosis, some of which do not require a focus of otosclerosis to abut the cochlear endosteal layer. The interest in identifying whether a focus of otosclerosis involves the cochlear endosteum comes from multiple previous studies correlating elevated bone thresholds to hyalin deposition in the spiral ligament (1–3). This hyalinization occurs adjacent to otosclerotic foci in the cochlear bone and has also been associated with atrophy of the adjacent stria vascularis. Immunostaining of human temporal bones with hyaline deposition in the spiral ligament has demonstrated decreased Na+, K+ ATPase in the adjacent stria vascularis, which may play a role in the associated sensorineural hearing loss seen in these patients (4). It is doubtful that any of the 3 cases of false-positive otosclerosis on CT represented end-stage histologic otic capsule otosclerosis. The clinical and audiologic histories of these 3 patients were not consistent with pure cochlear otosclerosis. One patient had a vestibular schwannoma with progressive profound sensorineural hearing loss. The second patient had normal hearing, with the exception of mild high-frequency sensorineural hearing loss appropriate for age. This temporal bone was acquired because the patient’s contralateral ear had Ménière’s disease. The third temporal bone came from a patient with chronic otitis media. She had a mixed hearing loss that could be explained by the history and histopathologic findings consistent with chronic otitis media. We reexamined these specimens and found no evidence of other foci of otosclerosis throughout the otic capsule or in the adjacent area. Alicia Marie Quesnel M.D. Department of Otolaryngology Massachusetts Eye and Ear Infirmary Boston, Massachusetts, U.S.A. Department of Otology and Laryngology Harvard Medical School Boston, Massachusetts, U.S.A. Gul Moonis M.D. Department of Radiology Massachusetts Eye and Ear Infirmary Harvard Medical School Boston, Massachusetts, U.S.A. Department of Radiology Beth Israel Deaconess Medical Center Boston, Massachusetts, U.S.A. Jason Appel M.D. Department of Radiology Massachusetts Eye and Ear Infirmary Harvard Medical School Boston, Massachusetts, U.S.A. Jennifer T. O’Malley B.A. Department of Otolaryngology Massachusetts Eye and Ear Infirmary Boston, Massachusetts, U.S.A. Department of Otology and Laryngology Harvard Medical School Boston, Massachusetts, U.S.A. Hugh D. Curtin M.D. Department of Radiology Massachusetts Eye and Ear Infirmary Harvard Medical School Boston, Massachusetts, U.S.A. Michael J. McKenna M.D. Department of Otolaryngology Massachusetts Eye and Ear Infirmary Boston, Massachusetts, U.S.A. Department of Otology and Laryngology Harvard Medical School Boston, Massachusetts, U.S.A. The authors disclose no conflicts of interest.

Loss of osteoprotegerin expression in the inner ear causes degeneration of the cochlear nerve and sensorineural hearing loss

Osteoprotegerin (OPG) is a key regulator of bone remodeling. Mutations and variations in the OPG gene cause many human diseases that are characterized by not only skeletal abnormalities but also poorly understood hearing loss: Paget's disease, osteoporosis, and celiac disease. To gain insight into the mechanisms of hearing loss in OPG deficiency, we studied OPG knockout (Opg−/−) mice. We show that they develop sensorineural hearing loss, in addition to conductive hearing loss due to abnormal middle-ear bones. OPG deficiency caused demyelination and degeneration of the cochlear nerve in vivo. It also activated ERK, sensitized spiral ganglion cells (SGC) to apoptosis, and inhibited proliferation and survival of cochlear stem cells in vitro, which could be rescued by treatment with exogenous OPG, an ERK inhibitor, or bisphosphonate. Our results demonstrate a novel role for OPG in the regulation of SGC survival, and suggest a mechanism for sensorineural hearing loss in OPG deficiency.

Inner Ear Changes in Mucopolysaccharidosis Type I/Hurler Syndrome

Mucopolysaccharidosis type I/Hurler syndrome is an autosomal recessive disease caused by a deficiency of α-L-iduronidase activity. Recurrent middle ear infections and hearing loss are common complications in Hurler syndrome. Although sensorineural and conductive components occur, the mechanism of sensorineural hearing loss has not been determined. The purpose of this study is to evaluate the quantitative inner ear histopathology of the temporal bones of patients with Hurler syndrome. Eleven temporal bones from 6 patients with Hurler syndrome were examined. Age-matched healthy control samples consisted of 14 temporal bones from 7 cases. Temporal bones were serially sectioned in the horizontal plane and stained with hematoxylin and eosin. The number of spiral ganglion cells, loss of cochlear hair cells, area of stria vascularis, and cell density of spiral ligament were evaluated using light microscopy. There was no significant difference between Hurler syndrome and healthy controls in the number of spiral ganglion cells, area of stria vascularis, or cell density of spiral ligament. The number of cochlear hair cells in Hurler syndrome was significantly decreased compared with healthy controls. Auditory pathophysiology in the central nerve system in Hurler syndrome remains unknown; however, decreased cochlear hair cells may be one of the important factors for the sensorineural component of hearing loss.

A Novel Animal Model of Hearing Loss Caused by Acute Endoplasmic Reticulum Stress in the Cochlea

Many stimuli such as ischemia, hypoxia, heat shock, amino acid starvation, and gene mutation, exhibit a cellular response called endoplasmic reticulum (ER) stress. ER stress induces expression of a series of genes, leading to cell survival or apoptosis. Previously, we found that in an animal model of hearing loss caused by acute mitochondrial dysfunction, several ER stress markers including C/EBP homologous protein were induced in the cochlear lateral wall. To elucidate the mechanism of hearing loss caused by ER stress, we established a novel animal model of hearing loss by perilymphatic perfusion of tunicamycin, an ER stress activator that inhibits N-acetylglucosamine transferases. Subacute and progressive hearing loss was observed at all sound frequencies studied, and stimulation of ER stress marker genes was noted in the cochlea. The outer hair cells were the most sensitive to ER stress in the cochlea. Electron microscopic analysis demonstrated degeneration of the subcellular organelles of the inner hair cells and nerve endings of the spiral ganglion cells. This newly established animal model of hearing loss from ER stress will provide additional insight into the mechanism of sensorineural hearing loss.

Molecular and hereditary mechanisms of sensorineural hearing loss with focus on selected endocrinopathies

Hearing loss is one of the most widespread sensory disorders. The incidence of deafness in general population is 1:1000 newborns. About one half of the cases of the congenital sensorineural hearing loss (SNHL) is inherited. Recessive mutations in the gap junction beta 2 (GJB2) gene are the most common genetic causes of the nonsyndromic SNHL. The GJB2 encodes a protein connexin 26 which forms a subunit of gap junction essential for the correct function of the inner ear. The syndromic SNHL is associated with a wide range of other symptoms, which encompass also dysfunctions of endocrine organs. The Pendred syndrome associated with the hearing impairment is characterized by a prelingual, bilateral sever to profound SNHL, goiter, and iodine organification defect. It is an autosomal recessive disorder, which develops due to mutations in pendrin, an anion channel encoded by SLC26A4 gene. Another important type of syndromic hearing loss is the Maternally Inherited Diabetes and Deafness syndrome, which is caused by several mitochondrial DNA mutations. These mutations are clinically manifested by a hearing impairment with development of the diabetes in the adult age. Hearing impairment occurs during puberty when sensation of high frequency tones is affected following with further progress to profound bilateral sensorineural hearing impairment in the whole frequency range. This review deals with the molecular mechanisms of common genetic causes of the hereditary SNHL along with the selected endocrinopathies emphasizing that the DNA analyses along with the functional studies significantly contribute to the early SNHL diagnosis followed by personalized therapy and genetic counseling.

Otoprotectant Minimizes Hearing Defects Caused by Pseudomonas aeruginosa Exotoxin A

Exotoxin A, produced by Pseudomonas aeruginosa (PaExoA), penetrates from the middle ear in to the cochlea and causes sensorineural hearing loss (SNHL). In this investigation we studied electrophysiological changes in the albino rat following instillation of PaExoA and NG-nitro-L-arginine methyl ester (L-NAME), a known inhibitor of nitric oxide synthesis, into the middle ear. Hearing thresholds were measured by auditory brainstem response (ABR) technique. Latency/intensity curves were constructed to distinguish between cochlear and conductive components of hearing loss. PaExoA caused damage to cochleae and SNHL, mainly at high frequencies. This impairment was blocked by L-NAME. It would appear that nitric oxide may be a significant link in the mechanism of SNHL caused by bacterial toxin. L-NAME acts as an otoprotectant against the deleterious action of PaExoA.

Is the round window membrane a portal for bacterial toxins? A putative mechanism for sensorineural hearing loss following acute otitis media

Aim: To investigate the hypothesis that bacterial toxins produced in the middle ear during acute otitis media (AOM), travel via the round window membrane (RWM) to cause cochlear damage and hence sensorineural hearing loss (SNHL). Methods: We investigated toxins produced by the two most common pathogens isolated from middle ear effusions in children. These were Pneumolysin, a product of S. pneumoniae and a cytoplasmic extract of Haemophilus influenza. Both electrophysiological measurements and morphological investigations were made after these toxins were placed on the RWM of guinea pigs. Control experiments were done using artificial perilymph as a substitute for the toxins. In each experiment one of the cochleas served as an internal control. Results: Losses in both the Cochlear Microphonics (CM) and Compound Action Potential (CAP) were observed indicating impaired hair cell function resulting in SNHL. Morphological studies showed hair cell destruction. Examination of the RWM exposed to pneumolysin showed disruption of this three-layered structure. Conclusions: The RWM is a probable portal for access to the inner ear by substances produced during AOM. Sensorineural hearing loss could result from the type of damage observed. More experiments are needed to verify this hypothesis and to determine the extent of damage that can be caused by these substances, especially with regard to the position of the damaged hair cells. Most of the damage observed occurred in the basal turn. Careful audiological examination (especially at high frequencies) of children who suffer with AOM might reveal a population of children with sensorineural hearing loss which might otherwise go undetected.

Possible role of peptides derived from otosclerotic bone in the mechanism of sensorineural hearing loss.

Otosclerotic stapes footplates, superstructures and temporal cortical bones were extracted with 0.25 M guanidine X HCl 0.5 M EDTA (pH 7.4) solution. The extracted non-collagenous peptides/proteins were separated chromatographically on a Sephadex G-25 microcolumn. The peptide composition of the bone samples were compared by capillary analytical isotachophoresis (ITP) in the molecular mass range 0.3-5 kD. The otosclerotic stapes footplate contained 13 ITP subfractions, while the stapes superstructures and cortical bone contained only 9 and 10, respectively. An otosclerosis-specific ITP subfraction was also detected in the stapes footplate, but not in the stapes superstructure or cortical bone. This subfraction was previously demonstrated in the otosclerotic perilymph as well. Four ITP subfractions occurred common in the otosclerotic stapes footplate, the superstructure and the cortical bone. Two of these common subfractions were not found in the cortical bone peptide extract, but all of them revealed higher than normal levels in the otosclerotic perilymph.