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Sci Transl Med. 2015 Jul 29;7(298):298ra118. doi: 10.1126/scitranslmed.aac5546.

Endotoxemia-mediated inflammation potentiates aminoglycoside-induced ototoxicity.

Author information

1
Oregon Hearing Research Center, Department of Otolaryngology, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA. Department of Otorhinolaryngology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, 173-82 Kumiro, Bundang-gu, Seongnam 463-707, Republic of Korea.
2
Oregon Hearing Research Center, Department of Otolaryngology, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA.
3
Oregon Hearing Research Center, Department of Otolaryngology, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA. Department of Otology and Skull Base Surgery, Eye Ear Nose and Throat Hospital, Fudan University, Shanghai 200031, China.
4
Oregon Hearing Research Center, Department of Otolaryngology, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA. steygerp@ohsu.edu.

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.

PMID:
26223301
PMCID:
PMC4534720
DOI:
10.1126/scitranslmed.aac5546
[Indexed for MEDLINE]
Free PMC Article

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