The loss of sensory hair cells in the cochlea is the major cause of sensorineural hearing loss, and inflammatory processes and immune factors in response to cochlear damage have been shown to induce hair cell apoptosis. The expression and function of Nfatc4 in the cochlea remains unclear. In this study, we investigated the expression of Nfatc4 in the mouse cochlea and explored its function using Nfatc4 −/− mice. We first showed that Nfatc4 was expressed in the cochlear hair cells. Cochlear hair cell development and hearing function were normal in Nfatc4 −/− mice, suggesting that Nfatc4 is not critical for cochlear development. We then showed that when the hair cells were challenged by ototoxic drugs Nfatc4 was activated and translocated from the cytoplasm to the nucleus, and this was accompanied by increased expression of Tnf and its downstream targets and subsequent hair cell apoptosis. Finally, we demonstrated that Nfatc4-deficient hair cells showed lower sensitivity to damage induced by ototoxic drugs and noise exposure compared to wild type controls. The Tnf-mediated apoptosis pathway was attenuated in Nfatc4-deficient cochlear epithelium, and this might be the reason for the reduced sensitivity of Nfatc4-deficient hair cells to injury. These findings suggest that the amelioration of inflammation-mediated hair cell apoptosis by inhibition of Nfatc4 activation might have significant therapeutic value in preventing ototoxic drug or noise exposure-induced sensorineural hearing loss.
Objective: Immunity is associated with acute low tone hearing loss. However, the exact pathophysiology of immunity-mediated acute low tone hearing loss remains unknown. In this study, we evaluated the presence, therapeutic effectiveness, and immunopathological mechanisms of anti-endothelial cell autoantibodies (AECEs) in patients with acute low-frequency hearing loss. Material and Methods: Forty-nine patients who were treated as inpatients having acute low-frequency hearing loss and additional symptoms, such as ear fullness, tinnitus, dizziness, or hyperacusis, were enrolled in this study. Serum samples from these patients were collected for laboratory serum autoimmunity detection, including AECAs, antinuclear antibodies, immunoglobulin, and circular immune complex. Therapeutic responses to combination therapy in short-term outcome and serum cytokine levels were compared between AECA-positive and AECA-negative patients. Results: Anti-endothelial cell autoantibodies–positive patients tended to show significantly less response to standard therapy compared with AECAs controls ( P < .05). Moreover, some serum cytokine levels elevated in both AECAs− and AECAs+ groups. Positive ratio of interleukin-8 and concentrations of macrophage inflammatory protein-1α were found higher in AECAs+ groups ( P < .05). Conclusion: The results supported that AECAs might wield influence on the short-term outcome of acute low-tone hearing loss (ALHL) treatment. Furthermore, AECA-mediated acute low-frequency hearing loss possibly involved dysregulation of inflammation process and release of cytokines.
Background. The precise mechanisms of nerve regeneration remain unclear. The potential of facial nerve regeneration and probable mechanisms involved following chronic facial nerve injury should be further studied. Methods. Adult male Wistar rats were used to model either (i) facial nerve injury (axotomy) or (ii) reinjury (chronic axotomy followed by a second axotomy within 5 months). The rats were housed in the animal facility of the Eye and ENT Hospital of Shanghai Medical School, Fudan University (Shanghai, China). Expression of Shh (sonic hedgehog) and growth-associated protein 43 (GAP43, a neuronal marker) was detected in bilateral facial nuclei using reverse transcriptase PCR, western blotting analysis, and immunohistochemistry. The number of surviving motoneurons was quantified, and facial nerve regeneration was examined using transmission electron microscopy. Results. Reinjury of the facial nerve 12 weeks after the first axotomy resulted in upregulation of GAP43 mRNA and protein expression in neurons ipsilateral to the axotomy; immunohistochemistry revealed that Shh expression was higher compared with control side facial nuclei at the same time point. GAP43 expression subsequently decreased. Conclusion. The greatest regeneration potential of the facial nerve occurred within 5 months following chronic axotomy in rats, and regeneration may involve the Shh signaling pathway.
Background The transcription factor Sox2 plays important roles in the developmental processes of multiple organs and tissues. However, whether Sox2 can protect mature or terminally differentiated cells against injury is still unknown. Methods We investigated the roles of Sox2 in cochlear hair cells, which are terminally differentiated cells, using conditional transgenic mice and several hearing loss models. Results Sox2 overexpression dramatically mitigated the degree of cochlear hair cell loss when exposed to ototoxic drugs. Noise-induced apoptosis of cochlear hair cells and hearing loss were also significantly alleviated by Sox2 overexpression. Notably, noise-induced upregulation of pro-inflammatory factors such as TNF-α and IL6 was inhibited by Sox2 overexpression. Then we used lipopolysaccharide to clarify the effect of Sox2 on cochlear inflammation, and Sox2 overexpression significantly inhibited lipopolysaccharide-induced upregulation of pro-inflammatory factors and alleviated inflammation-related cochlear hair cell death. Conclusions These results demonstrate a novel protective role of Sox2 in mature and terminally differentiated cochlear hair cells by inhibiting inflammation.
Hidden hearing loss (HHL), an auditory dysfunction that has gained much recent attention, has the hallmarks of speech discrimination and intelligibility deficits with normal or near-normal hearing thresholds. The pathological mechanisms of HHL are complicated and are not yet fully understood. HHL can be resulted from disorders of the central nervous system such as auditory cortex, and/or pathological changes of inner ear. Thus far, 2 pathological phenomena, synaptopathy and auditory nerve demyelination, have been reported as underlying causes of otogenic HHL. Here, we review the clinical and physiological characteristics of HHL as well as the molecular pathological mechanisms of otogenic HHL and aim to allude to potential therapy targets for clinical applications in the future.
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