The majority of acquired hearing loss, including presbycusis, is caused by irreversible damage to the sensorineural tissues of the cochlea. This article reviews the intracellular mechanisms that contribute to sensorineural damage in the cochlea, as well as the survival signaling pathways that can provide endogenous protection and tissue rescue. These data have primarily been generated in hearing loss not directly related to age. However, there is evidence that similar mechanisms operate in presbycusis. Moreover, accumulation of damage from other causes can contribute to age-related hearing loss (ARHL). Potential therapeutic interventions to balance opposing but interconnected cell damage and survival pathways, such as antioxidants, anti-apoptotics, and pro-inflammatory cytokine inhibitors, are also discussed.

Objective

Tinnitus has been the No. 1 disability at the Veteran Administration for the last 15 years, yet its interaction with hearing loss secondary to etiologies such as age, noise trauma, and traumatic brain injuries remains poorly characterized. Our objective was to analyze hearing loss and tinnitus, including audiogram data, of the Million Veteran Program within the context of military exposures in an aging population.

Design

Health records, questionnaires, audiograms, and military data were aggregated for 758,005 Veteran participants in the Million Veteran Program 2011 to 2020, with relative risks (RR) calculated for ancestries, sex, hearing loss and military exposures such as combat, blast, and military era served. A multivariate model with significant demographic measures and exposures was then analyzed. Next, audiogram data stratified by sex were compared for those with and without tinnitus by two methods: first, mean thresholds at standard frequencies were compared to thresholds adjusted per ISO 7029:2000E age and sex formulae. Second, levels for those ≤40 years of age were compared with those 41 and older. Finally, a proportional hazards model was examined to ascertain the timing between the onset of tinnitus and hearing loss, calculated separately for electronic health record diagnoses (ICD) and self-report.

Results

Tinnitus was either self-reported, diagnosed, or both in 37.5% (95% CI, 37.4 to 37.6), mean age 61.5 (95% CI, 61.4 to 61.5), range 18 to 112 years. Those with hearing loss were 4.15 times (95% CI, 4.12 to 4.15) as likely to have tinnitus. Americans of African descent were less likely to manifest tinnitus (RR 0.61, 95% CI, 0.60 to 0.61), as were women (RR 0.65, 95% CI, 0.64 to 0.65). A multivariate model indicated a higher RR of 1.73 for traumatic brain injury (95% CI, 1.71 to 1.73) and daily combat noise exposure (1.17, 95% CI, 1.14 to 1.17) than age (0.998, 95% CI, 0.997 to 0.998). Subjects ≤40 years of age had small but significantly elevated hearing thresholds through all standard frequencies compared to Veterans without tinnitus, and the effect of tinnitus on hearing thresholds diminished with age. In the hazard model, those >40 with new onset of tinnitus were at risk for hearing loss sooner and with greater incidence than those who were younger. The rate of hearing loss following tinnitus approached 100%. In contrast, only approximately 50% of those who self-reported hearing loss initially were at risk for later hearing loss, in contrast to ICD comparison, where those with ICD of hearing loss were more likely to sustain an ICD of tinnitus subsequently.

Conclusions

Evidence suggests that the occurrence of tinnitus in the military is more closely related to environmental exposures than to aging. The finding that tinnitus affects hearing frequencies across the audiogram spectrum suggests an acoustic injury independent of tonotopicity. Particularly for males >40, tinnitus may be a harbinger of audiologic damage predictive of later hearing loss.

Abstract Background The mechanisms that consolidate neural circuitry are a major focus of neuroscience. In the mammalian cochlea, the refinement of spiral ganglion neuron (SGN) innervation to the inner hair cells (by type I SGNs) and the outer hair cells (by type II SGNs) is accompanied by a 25% loss of SGNs. Results We investigated the segregation of neuronal loss in the mouse cochlea using β-tubulin and peripherin antisera to immunolabel all SGNs and selectively type II SGNs, respectively, and discovered that it is the type II SGN population that is predominately lost within the first postnatal week. Developmental neuronal loss has been attributed to the decline in neurotrophin expression by the target hair cells during this period, so we next examined survival of SGN sub-populations using tissue culture of the mid apex-mid turn region of neonatal mouse cochleae. In organotypic culture for 48 hours from postnatal day 1, endogenous trophic support from the organ of Corti proved sufficient to maintain all type II SGNs; however, a large proportion of type I SGNs were lost. Culture of the spiral ganglion as an explant, with removal of the organ of Corti, led to loss of the majority of both SGN sub-types. Brain-derived neurotrophic factor (BDNF) added as a supplement to the media rescued a significant proportion of the SGNs, particularly the type II SGNs, which also showed increased neuritogenesis. The known decline in BDNF production by the rodent sensory epithelium after birth is therefore a likely mediator of type II neuron apoptosis. Conclusion Our study thus indicates that BDNF supply from the organ of Corti supports consolidation of type II innervation in the neonatal mouse cochlea. In contrast, type I SGNs likely rely on additional sources for trophic support.

Otitis media (OM) is a common disease in young children, accounting for more office visits and surgeries than any other pediatric condition. It is associated with an estimated cost of five billion dollars annually in the USA. Moreover, chronic and recurrent middle ear (ME) disease leads to hearing loss during critical periods of language acquisition and learning leading to delays in reaching developmental milestones and risking permanent damage to the ME and inner ear in severe cases. Therefore, research to understand the disease pathogenesis and identify new therapeutics is important. Although OM is a multifactorial disease, targeting the molecular mechanisms that drive inflammation and OM resolution is critical. In this review, we discuss the current evidence suggesting that innate immune receptors and effectors play key roles in OM by mediating both the ME inflammatory responses and recovery.

Viral infections have already been implicated with otitis media and sudden sensorineural hearing loss. However, the pathophysiology of COVID-19 as it relates to otologic disorders is not well-defined. With the spread of SARS-CoV-2, it is important to evaluate its colonization of middle ear mucosa. Middle ear and nasal tissue samples for quantitative RT-PCR and histologic evaluations were obtained from post-mortem COVID-19 patients and non-diseased control patients. Here we present evidence that SARS-CoV-2 colonizes the middle ear epithelium and co-localizes with the primary viral receptor, angiotensin-converting enzyme 2 (ACE2). Both middle ear and nasal epithelial cells show relatively high expression of ACE2, required for SARS-CoV-2 entry. The epithelial cell adhesion molecule (EpCAM) was use as a biomarker of epithelia. Furthermore, we found that the viral load in the middle ear is lower than that present in the nasal cavity.

Otitis media (OM) is a common pediatric disease for which systemic antibiotics are often prescribed. While local treatment would avoid the systemic treatment side-effects, the tympanic membrane (TM) represents an impenetrable barrier unless surgically breached. We hypothesized that the TM might harbor innate biological mechanisms that could mediate trans-TM transport. We used two M13-bacteriophage display biopanning strategies to search for mediators of trans-TM transport. First, aliquots of linear phage library displaying 10(10th) 12mer peptides were applied on the TM of rats with active bacterial OM. The middle ear (ME) contents were then harvested, amplified and the preparation re-applied for additional rounds. Second, the same naïve library was sequentially screened for phage exhibiting TM binding, internalization and then transit. Results revealed a novel set of peptides that transit across the TM to the ME in a time and temperature dependent manner. The peptides with highest transport capacities shared sequence similarities. Historically, the TM was viewed as an impermeable barrier. However, our studies reveal that it is possible to translocate peptide-linked small particles across the TM. This is the first comprehensive biopanning for the isolation of TM transiting peptidic ligands. The identified mechanism offers a new drug delivery platform into the ME.

Background

Innate immunity and tissue proliferation play important roles in otitis media (OM), the most common disease of childhood. CJUN terminal kinase (JNK) is potentially involved in both processes.

Results

Genes involved in both innate immune and growth factor activation of JNK are upregulated during OM, while expression of both positive and negative JNK regulatory genes is altered. When compared to wildtypes (WTs), C57BL/6 mice deficient in JNK1 exhibit enhanced mucosal thickening, with delayed recovery, enhanced neutrophil recruitment early in OM, and delayed bacterial clearance. In contrast, JNK2-/- mice exhibit delayed mucosal hyperplasia that eventually exceeds that of WTs and is slow to recover, delayed recruitment of neutrophils, and failure of bacterial clearance.

Conclusions

The results suggest that JNK1 and JNK2 play primarily opposing roles in mucosal hyperplasia and neutrophil recruitment early in OM. However, both isoforms are required for the normal resolution of middle ear infection.

Otitis media (OM) is the most prevalent childhood disease in developed countries. Involvement of innate immunity mediated by Toll-like receptors (TLRs) in OM has been implicated primarily in cell lines and by association studies of innate immune gene polymorphisms with OM prevalence. However, the precise role of innate immunity in OM is incompletely understood. We review recent research that has advanced our understanding of how innate immunity in the middle ear is mediated by the interaction of pathogen molecules with receptors such as the TLRs, leading to the activation of adaptor molecules and production of proinflammatory cytokines. TLR genes and signaling molecules are upregulated in OM in a murine model. Deletion of several key innate immune genes results in persistent OM in mice, coupled with an inability to clear bacterial infection from the middle ear. It is concluded that an intact innate immune signaling system is critical to recovery from bacterial OM.