Abstract
Objective: The mechanism by which sepsis-induced inflammation enhances aminoglycoside trafficking into the cochlea remains poorly understood. This study sought to determine if protein expression of inflammatory-mediated cytokines in the cochlea is modulated by systemic sepsis and/or drug treatment.
Method: Three groups of mice received 1 of the following treatments: gentamicin, lipopolysaccharide for sepsis induction, or both gentamicin and lipopolysaccharide. A fourth group served as controls. After sacrifice, cochleae were collected and homogenized for protein extraction. This was followed by an enzyme-linked immunosorbent assay for analysis of 16 inflammatory-mediated cytokines.
Results: There was substantial elevation in cochlear expression of multiple cytokines in mice treated with bacteria-derived lipopolysaccharide, with or without gentamicin. The most salient cytokines were interleukin-1α, interleukin-6, monocyte chemotactic protein-1, and macrophage inflammatory protein-α. Gentamicin alone did not induce a significant inflammatory response, compared to lipopolysaccharide. This suggests that in the cochlea, specific pro-inflammatory cytokines are massively produced during a systemic infection, but not in the presence of aminoglycosides as the sole insult. Given that these cytokines increase permeability across blood-endothelial barriers, permitting transendothelial migration of inflammatory cells, they may also enhance aminoglycoside trafficking and contribute to its ototoxicity.
Conclusion: Aminoglycosides are usually prescribed for prophylaxis or systemic bacterial infection. The latter induces a pro-inflammatory state that could enhance aminoglycoside uptake by cochlear tissues. Unveiling the mechanisms mediated by sepsis that contribute to cochlear uptake of aminoglycosides will aid the development of strategies to ameliorate or prevent this devastating side-effect.
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