ABSTRACT
Hearing loss is one of the most common sensory impairments in humans. Mouse mutant models helped us to better understand the mechanisms of hearing loss. Recently, we have discovered that the erlong (erl) mutation of the cadherin23 (Cdh23) gene leads to hearing loss due to hair cell apoptosis. In this study, we aimed to reveal the molecular pathways upstream to apoptosis in hair cells to exploit more effective therapeutics than an anti-apoptosis strategy. Our results suggest that endoplasmic reticulum (ER) stress is the earliest molecular event leading to the apoptosis of hair cells and hearing loss in erl mice. We also report that the ER stress inhibitor, Salubrinal (Sal), could delay the progression of hearing loss and preserve hair cells. Our results provide evidence that therapies targeting signaling pathways in ER stress development prevent hair cell apoptosis at an early stage and lead to better outcomes than those targeting downstream factors, such as tip-link degeneration and apoptosis.
Subject(s)
Cadherins/genetics , Cinnamates/pharmacology , Endoplasmic Reticulum Stress/drug effects , Hair Cells, Auditory/pathology , Hearing Loss/pathology , Thiourea/analogs & derivatives , Animals , Down-Regulation/drug effects , Endoplasmic Reticulum Chaperone BiP , Eukaryotic Initiation Factor-2/metabolism , Hair Cells, Auditory/drug effects , Hair Cells, Auditory/metabolism , Hair Cells, Auditory, Outer/drug effects , Hair Cells, Auditory, Outer/metabolism , Hair Cells, Auditory, Outer/pathology , Heat-Shock Proteins , Mice, Mutant Strains , Mutation/genetics , Phosphorylation/drug effects , Thiourea/pharmacology , Transcription Factor CHOP/metabolism , Unfolded Protein Response/drug effects , eIF-2 Kinase/metabolismABSTRACT
BACKGROUND: Toll like receptor 2 (TLR2) signaling can regulate the pathogenesis of otitis media (OM). However, the precise role of TLR2 signaling in OM has not been clarified due to the lack of an optimal animal model. Peptidoglycan-polysaccharide (PGPS) of the bacterial cell wall can induce inflammation by activating the TLR2 signaling. This study aimed at examining the pathogenic characteristics of OM induced by PGPS in Tlr2(-/-) mice, and the potential therapeutic effect of sodium aescinate (SA) in this model. METHODS: Wild-type (WT) and Tlr2(-/-) mice were inoculated with streptococcal PGPS into their middle ears (MEs) and treated intravenously with vehicle or SA daily beginning at 3days prior to PGPS for 6 consecutive days. The pathologic changes of individual mice were evaluated longitudinally. RESULTS: In comparison with WT mice, Tlr2(-/-) mice were susceptible to PGPS-induced OM. Tlr2(-/-) mice displayed greater hearing loss, tympanic membrane damage, ME mucosal thickening, longer inflammation state, cilia and goblet cell loss. SA-treatment decreased neutrophil infiltration, modulated TLR2-related gene expression and improved ciliary organization. CONCLUSIONS: PGPS induced a relatively stable OM in Tlr2(-/-) mice, providing a new model for OM research. Treatment with SA mitigated the pathogenic damage in the ME and may be valuable for intervention of OM.
