Endotoxemia-mediated inflammation potentiates aminoglycoside-induced ototoxicity

Ja Won Koo, Lourdes Quintanilla-Dieck, Meiyan Jiang, Jianping Liu, Zachary D. Urdang, Jordan J. Allensworth, Campbell P. Cross, Hongzhe Li, Peter S. Steyger

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

The ototoxic aminoglycoside antibiotics are essential to treat severe bacterial infections, particularly in neonatal intensive care units. Using a bacterial lipopolysaccharide (LPS) experimental model of sepsis, we tested whether LPS-mediated inflammation potentiates cochlear uptake of aminoglycosides and permanent hearing loss in mice. Using confocal microscopy and enzyme-linked immunosorbent assays, we found that low-dose LPS (endotoxemia) greatly increased cochlear concentrations of aminoglycosides and resulted in vasodilation of cochlear capillaries without inducing paracellular flux across the blood-labyrinth barrier (BLB) or elevating serum concentrations of the drug. Additionally, endotoxemia increased expression of both serum and cochlear inflammatory markers. These LPS-induced changes, classically mediated by Toll-like receptor 4 (TLR4), were attenuated in TLR4-hyporesponsive mice. Multiday dosing with aminoglycosides during chronic endotoxemia induced greater hearing threshold shifts and sensory cell loss compared to mice without endotoxemia. Thus, endotoxemia-mediated inflammation enhanced aminoglycoside trafficking across the BLB and potentiated aminoglycoside-induced ototoxicity. These data indicate that patients with severe infections are at greater risk of aminoglycoside-induced hearing loss than previously recognized.

Original languageEnglish (US)
Article number298ra118
JournalScience translational medicine
Volume7
Issue number298
DOIs
StatePublished - Jul 29 2015

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint Dive into the research topics of 'Endotoxemia-mediated inflammation potentiates aminoglycoside-induced ototoxicity'. Together they form a unique fingerprint.

  • Cite this

    Koo, J. W., Quintanilla-Dieck, L., Jiang, M., Liu, J., Urdang, Z. D., Allensworth, J. J., Cross, C. P., Li, H., & Steyger, P. S. (2015). Endotoxemia-mediated inflammation potentiates aminoglycoside-induced ototoxicity. Science translational medicine, 7(298), [298ra118]. https://doi.org/10.1126/scitranslmed.aac5546