title: Endotoxemia-mediated inflammation potentiates aminoglycoside-induced ototoxicity.
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.
authors.affiliation: 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.
authors.forename: Ja-Won
authors.initials: JW
authors.lastname: Koo
authors.affiliation: Oregon Hearing Research Center, Department of Otolaryngology, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Quintanilla-Dieck
authors.affiliation: Oregon Hearing Research Center, Department of Otolaryngology, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA.
authors.forename: Meiyan
authors.initials: M
authors.lastname: Jiang
authors.affiliation: 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.
authors.forename: Jianping
authors.initials: J
authors.lastname: Liu
authors.affiliation: Oregon Hearing Research Center, Department of Otolaryngology, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA.
authors.forename: Zachary D
authors.initials: ZD
authors.lastname: Urdang
authors.affiliation: Oregon Hearing Research Center, Department of Otolaryngology, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA.
authors.forename: Jordan J
authors.initials: JJ
authors.lastname: Allensworth
authors.affiliation: Oregon Hearing Research Center, Department of Otolaryngology, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA.
authors.forename: Campbell P
authors.initials: CP
authors.lastname: Cross
authors.affiliation: Oregon Hearing Research Center, Department of Otolaryngology, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA.
authors.forename: Hongzhe
authors.initials: H
authors.lastname: Li
authors.affiliation: Oregon Hearing Research Center, Department of Otolaryngology, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA. steygerp@ohsu.edu.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Steyger
mesh_terms: D000617:Aminoglycosides / Q000009:adverse effects; D000818:Animals; D019446:Endotoxemia / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D006319:Hearing Loss, Sensorineural / Q000139:chemically induced* / Q000209:etiology / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D000617:Aminoglycosides; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D051197:Toll-Like Receptor 4