Resolution of Cochlear Inflammation: Novel Target for Preventing or Ameliorating Drug-, Noise- and Age-related Hearing Loss

Abstract

A significant number of studies support the idea that inflammatory responses are intimately associated with drug-, noise- and age-related hearing loss (DRHL, NRHL and ARHL). Consequently, several clinical strategies aimed at reducing auditory dysfunction by preventing inflammation are currently under intense scrutiny. Inflammation, however, is a normal adaptive response aimed at restoring tissue functionality and homeostasis after infection, tissue injury and even stress under sterile conditions, and suppressing it could have unintended negative consequences. Therefore, an appropriate approach to prevent or ameliorate DRHL, NRHL and ARHL should involve improving the resolution of the inflammatory process in the cochlea rather than inhibiting this phenomenon. The resolution of inflammation is not a passive response but rather an active, highly controlled and coordinated process. Inflammation by itself produces specialized pro-resolving mediators with critical functions, including essential fatty acid derivatives (lipoxins, resolvins, protectins and maresins), proteins and peptides such as annexin A1 and galectins, purines (adenosine), gaseous mediators (NO, H2S and CO), as well as neuromodulators like acetylcholine and netrin-1. In this review article, we describe recent advances in the understanding of the resolution phase of inflammation and highlight therapeutic strategies that might be useful in preventing inflammation-induced cochlear damage. In particular, we emphasize beneficial approaches that have been tested in pre-clinical models of inflammatory responses induced by recognized ototoxic drugs such as cisplatin and aminoglycoside antibiotics. Since these studies suggest that improving the resolution process could be useful for the prevention of inflammation-associated diseases in humans, we discuss the potential application of similar strategies to prevent or mitigate DRHL, NRHL and ARHL.

The dual role of curcumin and ferulic acid in counteracting chemoresistance and cisplatin-induced ototoxicity

“…HO-1 has prominent antioxidant and anti-inflammatory properties 40 . Additionally, cisplatin-induced ROS generation is a key contributor to inflammation and apoptosis in cochlear cells 18,[41][42][43] , as demonstrated by NF-κB over-expression in cochlear structures in our in vivo model. NF-κB is another target for ROS 44 and redox-dependent and independent mechanisms have been proposed to explain NF-κB activation, both of which, by using different pathways, have NF-κB as a downstream target 45 .…”

Pathology and mechanisms of cochlear aging

“…The magnitude of ARHL could best be reduced by protection from noise exposure that directly leads to outer hair cell degeneration (Liberman & Kiang, ) and ultimately neuronal degeneration (Kujawa & Liberman, ) and inflammation (Hirose et al, ; Tornabene et al, ). Though not reviewed here, several groups are working on therapeutic, pharmaceutical strategies for addressing age‐related cochlear degeneration (Bielefeld, Tanaka, Chen, & Henderson, ; Frisina, Ding, Zhu, & Walton, ; Kalinec, Lomber, Urrutia, & Kalinec, ; Seidman, ; Seidman, Khan, Tang, & Quirk, ; Wan & Corfas, ) and the future might then see less debilitation from ARHL.…”

Aminoglycoside-Induced Cochleotoxicity: A Review

“…The potential mechanisms by which systemic inflammation enhances aminoglycoside-induced ototoxicity is discussed elsewhere in this Research Topic (Jiang et al, under review). Much further work is required to unravel how inflammation affects: (i) cochlear physiology; and (ii) repair of cochlear lesions following noise exposure or ototoxicity, as discussed elsewhere in this Research Topic (Kalinec et al, 2017 ).…”