Endotoxemia-mediated inflammation potentiates aminoglycoside-induced ototoxicity

被引：80

作者：

Koo, Ja-Won ^{[1
,2
]}

Quintanilla-Dieck, Lourdes ^{[1
]}

Jiang, Meiyan ^{[1
]}

Liu, Jianping ^{[1
,3
]}

Urdang, Zachary D. ^{[1
]}

Allensworth, Jordan J. ^{[1
]}

Cross, Campbell P. ^{[1
]}

Li, Hongzhe ^{[1
]}

Steyger, Peter S. ^{[1
]}

机构：

[1] Oregon Hlth & Sci Univ, Dept Otolaryngol, Oregon Hearing Res Ctr, Portland, OR 97239 USA

[2] Seoul Natl Univ, Bundang Hosp, Seoul Natl Univ Coll Med, Dept Otorhinolaryngol, Songnam 463707, South Korea

[3] Fudan Univ, Eye Ear Nose & Throat Hosp, Dept Otol & Skull Base Surg, Shanghai 200031, Peoples R China

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2015年 / 7卷 / 298期

基金：

新加坡国家研究基金会;

关键词：

BLOOD-BRAIN-BARRIER; CHILDHOOD HEARING IMPAIRMENT; COCHLEAR HAIR-CELLS; ACUTE-RENAL-FAILURE; GUINEA-PIG COCHLEA; STRIA VASCULARIS; FLUORESCENT GENTAMICIN; SENSORY CELLS; RISK-FACTORS; IN-VIVO;

D O I：

10.1126/scitranslmed.aac5546

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页数：13

共 88 条

[1] Astrocyte-endothelial interactions at the blood-brain barrier [J].