Systemic Lipopolysaccharide Induces Cochlear Inflammation and Exacerbates the Synergistic Ototoxicity of Kanamycin and Furosemide
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Aminoglycoside antibiotics are highly effective agents against gram-negative bacterial infections, but they cause adverse effects on hearing and balance dysfunction as a result of toxicity to hair cells of the cochlea and vestibular organs. While ototoxicity has been comprehensively studied, the contributions of the immune system, which controls the host response to infection, have not been studied in antibiotic ototoxicity. Recently, it has been shown that an inflammatory response is induced by hair cell injury. In this study, we found that lipopolysaccharide (LPS), an important component of bacterial endotoxin, when given in combination with kanamycin and furosemide, augmented the inflammatory response to hair cell injury and exacerbated hearing loss and hair cell injury. LPS injected into the peritoneum of experimental mice induced a brisk cochlear inflammatory response with recruitment of mononuclear phagocytes into the spiral ligament, even in the absence of ototoxic agents. While LPS alone did not affect hearing, animals that received LPS prior to ototoxic agents had worse hearing loss compared to those that did not receive LPS pretreatment. The poorer hearing outcome in LPS-treated mice did not correlate to changes in endocochlear potential. However, LPS-treated mice demonstrated an increased number of CCR2+ inflammatory monocytes in the inner ear when compared with mice treated with ototoxic agents alone. We conclude that LPS and its associated inflammatory response are harmful to the inner ear when coupled with ototoxic medications and that the immune system may contribute to the final hearing outcome in subjects treated with ototoxic agents.
KeywordsLPS monocyte macrophage cochlea inflammation ototoxicity
Many thanks to Drs. Mark Warchol and Alec Salt for careful feedback on the manuscript and to Dorina Kallojieri for assistance with statistical analysis. Funding sources supporting this work include NIH DC011315 and a research grant from the American Otological Society.
Conflict of Interest
None of the authors who have authored or provided materials for this work have a financial, personal, or other conflicting interest in the results of this research or publication of this work.
All authors had full access to the data in this study and take responsibility for the integrity and accuracy of the data analysis. Study concept and design: KH, KKO, RMR. Acquisition of data: SZL, KKO, KH. Analysis and interpretations of the data: KH, KKO, RMR. Writing of the manuscript: KH. Statistical analysis: KH. Funding awarded to: KH. Study supervision: KH.
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