Inner ear tissue remodeling and ion homeostasis gene alteration in murine chronic otitis media

Abstract

Hypothesis: Studies were designed to ascertain the impact of chronic middle ear infection on the numerous ion and water channels, transporters, and tissue remodeling genes in the inner and middle ear.

Background: Permanent sensorineural hearing loss is a significant problem resulting from chronic middle ear disease, although the inner ear processes involved are poorly defined. Maintaining a balanced ionic composition of endolymph in the inner ear is crucial for hearing; thus, it was hypothesized that this may be at risk with inflammation.

Methods: Inner and middle ear RNA collected separately from 6-month-old C3H/HeJ mice with prolonged middle ear disease were subjected to qRT-PCR for 8 common inflammatory cytokine genes, 24 genes for channels controlling ion (sodium, potassium, and chloride) and water (aquaporin) transport, tight junction claudins, and gap junction connexins, and 32 tissue remodeling genes. Uninfected Balb/c mice were used as controls.

Results: Significant increase in inner ear inflammatory and ion homeostasis (claudin, aquaporin, and gap junction) gene expression, and both upregulation and downregulation of tissue remodeling gene expression occurred. Alteration in middle ear ion homeostasis and tissue remodeling gene expression was noted in the setting of uniform upregulation of cytokine genes.

Conclusion: Chronic inflammatory middle ear disease can impact inner ear ion and water transport functions and induce tissue remodeling. Recognizing these inner ear mechanisms at risk may identify potential therapeutic targets to maintain hearing during prolonged otitis media.

Figure 1

Cytokine gene expression in inner ears of C3H/HeJ mice with inflamed or uninflamed MEs relating to Balb/c controls. Upregulation of all cytokine genes in the inner ear was seen showing that cells within the cochlea are expressing and secreting cytokines during chronic OM. All fold change values greater than two-fold over controls are considered significant (over solid line). None are < 0.5 x (below dotted line) in the inner ear ipsilateral to the infected middle ear. Error bars are standard of the mean (SEM).

Figure 2

Ion Homeostasis gene expression in inner ears of C3H/HeJ mice with inflamed or uninflamed MEs relating to Balb/c controls. Error bars are standard of the mean (SEM). Increased expression of ion homeostasis genes was seen at the highest levels with claudin 3, aquaporins 2, and 3, and gap junction Gjb3, suggesting that chronic middle ear disease leads to altered expression of ion homeostasis and transport functions in the inner ear.

Figure 3

Tissue remodeling gene expression in inner ears of C3H/HeJ mice with inflamed or uninflamed MEs relating to Balb/c controls. Error bars are standard of the mean (SEM). Tissue remodeling genes in the inner ear tissues were shown to have altered expression in the C3H mouse compared to controls, suggesting that chronic middle ear disease leads to altered expression of tissue remodeling genes in the inner ear, in a similar pattern to that seen in the middle ear.