Otitis media-induced cochlear immune response and opportunistic ototoxicity

Abstract

Lipopolysaccharide (LPS), an essential component of the bacterial endotoxin, activates tissue macrophages and triggers the release of inflammatory cytokines. In animal models, intratympanic (i.t.) injection of LPS is known to simulate acute otitis media (AOM) and modifies the structure and function of the inner ear. However, whether LPS-induced AOM modulates the uptake of ototoxic aminoglycosides in vivo is unclear. Here, we established an AOM mouse model to investigate the gentamicin uptake in the inner ear and the change of cochlear inflammation for pertaining ototoxicity mechanisms. We found that LPS-induced AOM switched on the cochlear inflammatory response, including macrophage infiltration and upregulation of pro-inflammation cytokines, and significantly enhanced the cochlear uptake of gentamicin. Potential mechanisms of enhanced drug uptake may include increased strial permeability due to acute middle-ear inflammation, resulting in higher drug concentration in the stria vascularis and the endolymph, and subsequently higher drug uptake by hair cells. Other possible mechanisms, such as the activation of specific candidate channels and endocytosis followed by inflammation, need to be further interrogated. In sum, this study improves our understanding of drug trafficking in the pathological cochlea and provides a reference for drug treatment of AOM while protecting the inner ear function.