Role of cysteinyl leukotriene signaling in a mouse model of noise-induced cochlear injury

Abstract

Noise-induced hearing loss is one of the most common types of sensorineural hearing loss. In this study, we examined the expression and localization of leukotriene receptors and their respective changes in the cochlea after hazardous noise exposure. We found that the expression of cysteinyl leukotriene type 1 receptor (CysLTR1) was increased until 3 d after noise exposure and enhanced CysLTR1 expression was mainly observed in the spiral ligament and the organ of Corti. Expression of 5-lipoxygenase was increased similar to that of CysLTR1, and there was an accompanying elevation of CysLT concentration. Posttreatment with leukotriene receptor antagonist (LTRA), montelukast, for 4 consecutive days after noise exposure significantly decreased the permanent threshold shift and also reduced the hair cell death in the cochlea. Using RNA-sequencing, we found that the expression of matrix metalloproteinase-3 (MMP-3) was up-regulated after noise exposure, and it was significantly inhibited by montelukast. Posttreatment with a MMP-3 inhibitor also protected the hair cells and reduced the permanent threshold shift. These findings suggest that acoustic injury up-regulated CysLT signaling in the cochlea and cochlear injury could be attenuated by LTRA through regulation of MMP-3 expression. This study provides mechanistic insights into the role of CysLTs signaling in noise-induced hearing loss and the therapeutic benefit of LTRA.

Mechanisms of sensorineural cell damage, death and survival in the cochlea

“…This cochlear damage due to a variety of causes can initiate the inflammatory cascade in the absence of infection. Noise-induced hearing loss has been found to induce inflammation as evidenced by the observation of pro-inflammatory cytokines (Wakabayashi et al, 2010 ), leukotrienes (Park et al, 2014 ) and leukocytes (Hirose et al, 2005 ; Tornabene et al, 2006 ) within the inner ear. Similarly, ototoxicity can also induce inner ear inflammation (Sato et al, 2008 , 2010 ; Dinh et al, 2013 ).…”

Effect of Specific Retinoic Acid Receptor Agonists on Noise-Induced Hearing Loss

“…Mice were continuously exposed to 110 dB peak equivalent SPL for one 3-h session. It was considered that noise exposure of 110 dB SPL for 3 h is reasonable to induce NIHL based on a review of the literature [5,9].…”

Gene expression profiling of the inner ear

“…Finally, the role of cysteinyl leukotriene signalling, which plays an important role during inflammation, has recently been studied in a mouse model of noise damage (Park et al. ). Expression of the cysteinyl leukotriene type 1 receptor (CysLTR1) was found to be increased in the organ of Corti 3 days after noise exposure.…”

“…Genes involved in the immune system or induced as a response to stress or stimuli were also altered in a study where gene expression was monitored in rats 1 h after cessation of noise exposure (Han et al 2012). Finally, the role of cysteinyl leukotriene signalling, which plays an important role during inflammation, has recently been studied in a mouse model of noise damage (Park et al 2014). Expression of the cysteinyl leukotriene type 1 receptor (CysLTR1) was found to be increased in the organ of Corti 3 days after noise exposure.…”