Inhibition of Cochlear HMGB1 Expression Attenuates Oxidative Stress and Inflammation in an Experimental Murine Model of Noise-Induced Hearing Loss.

Cheng-Ping Shih,Hao Wang,Yi-Chun Lin,Hsin-Chien Chen,Hang-Kang Chen,Chih-Hung Wang,Yuan-Yung Lin,Chao-Yin Kuo

doi:10.3390/cells10040810

Abstract

Noise-induced hearing loss (NIHL) is a common inner ear disease but has complex pathological mechanisms, one of which is increased oxidative stress in the cochlea. The high-mobility group box 1 (HMGB1) protein acts as an inflammatory mediator and shows different activities with redox modifications linked to the generation of reactive oxygen species (ROS). We aimed to investigate whether manipulation of cochlear HMGB1 during noise exposure could prevent noise-induced oxidative stress and hearing loss. Sixty CBA/CaJ mice were divided into two groups. An intraperitoneal injection of anti-HMGB1 antibodies was administered to the experimental group; the control group was injected with saline. Thirty minutes later, all mice were subjected to white noise exposure. Subsequent cochlear damage, including auditory threshold shifts, hair cell loss, expression of cochlear HMGB1, and free radical activity, was then evaluated. The levels of HMGB1 and 4-hydroxynonenal (4-HNE), as respective markers of reactive nitrogen species (RNS) and ROS formation, showed slight increases on post-exposure day 1 and achieved their highest levels on post-exposure day 4. After noise exposure, the antibody-treated mice showed markedly less ROS formation and lower expression of NADPH oxidase 4 (NOX4), nitrotyrosine, inducible nitric oxide synthase (iNOS), and intercellular adhesion molecule-1 (ICAM-1) than the saline-treated control mice. A significant amelioration was also observed in the threshold shifts of the auditory brainstem response and the loss of outer hair cells in the antibody-treated versus the saline-treated mice. Our results suggest that inhibition of HMGB1 by neutralization with anti-HMGB1 antibodies prior to noise exposure effectively attenuated oxidative stress and subsequent inflammation. This procedure could therefore have potential as a therapy for NIHL.

Highlights

Hearing handicaps arising from acoustic injury or noise trauma are a globally prevalent disability that manifests as hearing loss, tinnitus, the impairment of daily performance, and sleep disturbance [1]
We reported that the increased expression of cochlear high-mobility group box 1 (HMGB1) induced by noise-induced hearing loss (NIHL) was repressed by round window membrane-mediated dexamethasone treatment, suggesting that HMGB1 may be a useful marker of inflammation in NIHL [19]
Gene expression in primary cochlear cells with a dose-dependent effect (Figure 1C). These results implicated that inner ear sensory organs might be targeted by HMGB1-mediated inflammation or oxidative stress that contributes to cochlear injury after noise exposure

Summary

Introduction

Hearing handicaps arising from acoustic injury or noise trauma are a globally prevalent disability that manifests as hearing loss, tinnitus, the impairment of daily performance, and sleep disturbance [1]. Steady-state noise exposure causes metabolic overstimulation of factors like oxidative stress, inflammation, and apoptosis that are associated with NIHL [3,4,5]. Noise-associated oxidative stress in the cochlea is recognized as an important contributor to the pathogenesis of NIHL and may reflect a combination of overdriving of the mitochondria, glutamate excitotoxicity, and ischemia/reperfusion injury of the cochlear blood supply [3]. The end result of these processes is an increased generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and subsequent cellular DNA and protein damage. These changes lead to damage to organelles and triggering of apoptotic/necrotic cell death [3,5]

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