Systemic lipopolysaccharide induces cochlear inflammation and exacerbates the synergistic ototoxicity of kanamycin and furosemide.
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.
Department of Otolaryngology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO, 63110, USA, keiko_hirose@post.harvard.edu.
Keiko
K
Hirose
Song-Zhe
SZ
Li
Kevin K
KK
Ohlemiller
Richard M
RM
Ransohoff
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000633:toxicity; D000073883:CX3C Chemokine Receptor 1; D003051:Cochlea / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D015834:Cochlear Diseases / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004357:Drug Synergism; D007758:Ear, Inner / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D016057:Evoked Potentials, Auditory, Brain Stem / Q000502:physiology; D005665:Furosemide / Q000494:pharmacology / Q000633:toxicity*; D018072:Hair Cells, Auditory, Outer / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D006579:Heterozygote; D007249:Inflammation / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D007612:Kanamycin / Q000494:pharmacology / Q000633:toxicity*; D008070:Lipopolysaccharides / Q000009:adverse effects* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains / Q000235:genetics; D019707:Receptors, Chemokine / Q000235:genetics
D000900:Anti-Bacterial Agents; D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; D008070:Lipopolysaccharides; D019707:Receptors, Chemokine; D007612:Kanamycin; D005665:Furosemide