Intratympanic Lipopolysaccharide Elevates Systemic Fluorescent Gentamicin Uptake in the Cochlea

Abstract

Objectives/Hypothesis Lipopolysaccharide (LPS), a key component of bacterial endotoxins, activates macrophages and triggers the release of inflammatory cytokines in mammalian tissues. Recent studies have shown that intratympanic injection of LPS simulates acute otitis media (AOM) and results in morphological and functional changes in the inner ear. Here we established an AOM mouse model with LPS to investigate the uptake of ototoxic gentamicin in the inner ear, and elucidated the underlying mechanism by focusing on cochlear inflammation as a result of AOM. Study Design Preclinical rodent animal model. Methods Fluorescently tagged gentamicin (GTTR) was systemically administered to mice with AOM. Iba1‐positive macrophage morphology and inner ear cytokine profile were evaluated by immunofluorescence technique and a mouse cytokine array kit, respectively. Results We observed characteristic symptoms of AOM in the LPS‐treated ears with elevated hearing thresholds indicating a conductive hearing loss. More importantly, the LPS‐induced AOM activated cochlear inflammatory responses, manifested by macrophage infiltration, particularly in the organ of Corti and the spiral ligament, in addition to the up‐regulation of proinflammatory cytokines. Meanwhile, GTTR uptake in the stria vascularis and sensory hair cells from all the LPS‐treated ears was significantly enhanced at 24, 48, and 72‐hour post‐treatment, as the most prominent enhancement was observed in the 48‐hour group. Conclusion In summary, this study suggests that the pathological cochlea is more susceptible to ototoxic drugs, including aminoglycosides, and justified the clinical concern of aminoglycoside ototoxicity in the AOM treatment. Laryngoscope, 131:E2573–E2582, 2021

Protection of lipopolysaccharide-induced otic injury by a single dose administration of a novel dexamethasone formulation

“…SPT-2101-treated rats also maintained the protein levels of NRF2 and NLRP3, two key modulators of in ammatory and stress responses (40,41). Proin ammatory cytokines are involved in chemotaxis and immune cell in ltration, which is common following LPS exposure (45). Accordingly, SPT-2101 reduced in ltration of IBA1 + macrophages in the lateral wall, speci cally in the type IV brocyte area of the spiral ligament, as well as in the spiral ganglion.…”

“…Administration of LPS directly into the scala media of guinea pigs, an experimental model of immune-mediated Meniere's disease, induced severe hydrops, immune cell in ltration, and permanent hearing loss (11). LPS-induced hearing loss is not generally associated with hair cell loss (45). Indeed, loss of the endocochlear potential due to perturbation of vascular permeability and ion transport in the stria vascularis is considered as the main cause of LPSinduced hearing thresholds shifts (14,19).…”

Sound conditioning strategy promoting paracellular permeability of the blood‐labyrinth‐barrier benefits inner ear drug delivery

“…Structural associations and interactions between these components control vascular permeability and maintain the integrity of BLB. [4][5][6] Several external factors can modulate the permeability of the BLB including diuretics, 7,8 inflammation, [9][10][11] and acoustic trauma. [9][10][11] For instance, furosemide can promote the cochlear concentrations of cisplatin and aminoglycosides by elevating BLB permeability, and further increases ototoxic effects when administered concomitantly.…”

“…[4][5][6] Several external factors can modulate the permeability of the BLB including diuretics, 7,8 inflammation, [9][10][11] and acoustic trauma. [9][10][11] For instance, furosemide can promote the cochlear concentrations of cisplatin and aminoglycosides by elevating BLB permeability, and further increases ototoxic effects when administered concomitantly. 7,12 Acoustic trauma could increase the permeability of BLB by either damaging the tight junctions (TJs) between adjacent endothelial cells, claudin-5 and occludin, 13 or upregulating matrix metalloproteinases (MMP-2 and -9) which are known to be capable of degrading TJ proteins.…”

Effects of Combined Gentamicin and Furosemide Treatment on Cochlear Macrophages

“…This raises concern when clinicians prescribe them more aggressively, such as in the case of cystic fibrosis patients [2]. The ototoxic risk can be further elevated in either local [3] or systemic [4] infections. In the biomedical research setting, scientists have been utilizing the ototoxic properties of aminoglycosides to deafen research animals and subsequently investigate candidate therapeutic strategies to cure hearing loss, including regenerative [5][6][7] and prosthetic [8,9] approaches.…”