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Proc. Natl. Acad. Sci. USA, published ahead of print June 23, 2014 | doi:10.1073/pnas.1402261111 Role of cysteinyl leukotriene signaling in a mouse model of noise-induced cochlear injury

Abstract

Jung-Sub Park^a,b,c,d, Seo-Jun Kang^a,c,d, Mi-kyoung Seo^d,e, Ilo Jou^a,c,d, Hyun Goo Woo^d,e, and Sang Myun Park^a,c,d,1

^aDepartment of Pharmacology,
^bDepartment of Otolaryngology,
^cNeuroscience Graduate Program, Department of Biological Sciences,
^dChronic Inflammatory Disease Research Center, and
^eDepartment of Physiology, Ajou University School of Medicine, Yeongtong-gu, Suwon 443-380, Korea

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.

¹To whom correspondence should be addressed.

Author contributions: J.-S.P. and S.M.P. designed research; J.-S.P., S.-J.K., and M.-k.S. performed research; J.-S.P., S.-J.K., M.-k.S., I.J., H.G.W., and S.M.P. analyzed data; and J.-S.P. and S.M.P. wrote the paper.

논문정보

형식Research article
게재일2014년 06월 (BRIC 등록일 2014-07-02)
연구진국내 연구진
분야 의약학 > 신경의학

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