Potential Mechanisms Underlying Inflammation-Enhanced Aminoglycoside-Induced Cochleotoxicity

Abstract

Aminoglycoside antibiotics remain widely used for urgent clinical treatment of life-threatening infections, despite the well-recognized risk of permanent hearing loss, i.e., cochleotoxicity. Recent studies show that aminoglycoside-induced cochleotoxicity is exacerbated by bacteriogenic-induced inflammation. This implies that those with severe bacterial infections (that induce systemic inflammation), and are treated with bactericidal aminoglycosides are at greater risk of drug-induced hearing loss than previously recognized. Incorporating this novel comorbid factor into cochleotoxicity risk prediction models will better predict which individuals are more predisposed to drug-induced hearing loss. Here, we review the cellular and/or signaling mechanisms by which host-mediated inflammatory responses to infection could enhance the trafficking of systemically administered aminoglycosides into the cochlea to enhance the degree of cochleotoxicity over that in healthy preclinical models. Once verified, these mechanisms will be potential targets for novel pharmacotherapeutics that reduce the risk of drug-induced hearing loss (and acute kidney damage) without compromising the life-saving bactericidal efficacy of aminoglycosides.

Keywords: aminoglycosides; bacteriogenic; gentamicin; infection; inflammation; ototoxicity; sepsis; virogenic.

FIGURE 1

Cross-section of the cochlear duct, with perilymph-filled scala vestibuli and scala tympani (pale blue) separated from the endolymphatic scala media (white) by tight junctions between adjacent cells (thicker black line) in Reissner’s membrane, the stria vascularis (light gray) and reticular lamina of the organ of Corti on the basilar membrane. Within the organ of Corti are four longitudinal rows of sensory hair cells (blue), under the tectorial membrane, and innervated by afferent and efferent fibers (blue lines). The highly vascularized stria vascularis has capillaries (pink circles) lined by tight junction-coupled endothelial cells (black lines enclosing pink circles) that form the BLB. Circulating aminoglycosides preferentially cross the BLB into the stria vascularis (1) and are cleared into endolymph (2) prior to entering hair cells across their apical membranes (3). Aminoglycosides also enter perilymph, but this trafficking route is not a major contributor to hair cell uptake in healthy guinea pigs. Diagram not to relative scale, and adapted with permission from Macmillan Publishers Ltd., Li and Steyger (2011).

FIGURE 2

Three weeks after chronic [lipopolysaccharides (LPS) or saline] exposure with or without twice daily kanamycin dosing, ABR threshold shifts for mice treated with LPS-only (red) were not different from saline-treated mice (DPBS, gray). Kanamycin alone (700 mg/kg, twice daily; blue) induced a small but significant PTS at only 32 kHz (^∗P < 0.01) compared to saline-treated mice (gray). that received LPS plus kanamycin (purple) had significant PTS at 16, 24 (^∗∗P < 0.01), and 32 kHz (P < 0.05) compared to mice treated with kanamycin, saline or LPS only (^∗∗P < 0.01). Mice receiving LPS plus kanamycin also had significant PTS at 12 kHz compared to mice treated with DPBS or LPS only, or LPS-only mice at 8 kHz. Error bars = SD. Figure adapted from Koo et al., 2015, with permission from Science/American Association for the Advancement of Science.

FIGURE 3

(A) Overview of human TLRs activated by exogenous and endogenous ligands, such as fragmented DNA from necrotic cells; adapted by permission from Macmillan Publishers Ltd, Nature Reviews Gastroenterology and Hepatology, 2006, vol. 3, pp..390–407, Sartor (2006). (B) Schematic of TLR4 and TLR3 signaling pathways. LPS binding to membranous TLR4 activates the MyD88-dependent and MyD88-independent signaling pathways via different adaptor proteins. MyD88-dependent pathway activates IRAK-4, transforming TAK1 and TAK-binding protein 2 or 3 (TAB2/3) to stimulate downstream MAPK, and transcription and expression of pro-inflammatory cytokines (e.g., TNFα, IL-1α, IL-1β, IL-2, IL-6, IL-12). The MyD88-independent pathway activates IκB kinase (IKK) complex, releasing NF-κB to translocate to the nucleus and transcribe genes that express type 1 interferons. Viral double-stranded (dsRNA) binds TLR3 on cell or endosomal membranes and recruit the adaptor molecule TRIF. This initiates two pathways via IKKα,β and TRAF-3. IKKα,β activates NF-κB subunits which translocate to the nucleus to trigger transcription of genes encoding pro-inflammatory cytokines. Alternatively, TRIF stimulates TRAF3 to activate TBK1/IKKi and phosphorylate transcription factor IRF-3 and IRF-7. After homodimerization, IRF-3 and-IRF-7 translocate to the nucleus to transcribe type I IFNα,β. Secretion of type 1 IFNα,β leads to further transcription and expression of pro-inflammatory cytokines. Both schematics are not to scale.

FIGURE 4

To cross the strial BLB, aminoglycosides must first enter endothelial cells (dark gray), and permeate through gap junctions into intermediate cells (I) and/or basal cells (B). Aminoglycosides could clear endothelial, intermediate and basal cells via transporters, exchangers, and/or cation channels, or by exocytosis of endosomes (not shown), into the intra-strial space. Aminoglycosides are taken up by marginal cells across their basolateral membranes, presumptively by ATPases, exchangers, and transporters (and ion channels?). Once in marginal cells, aminoglycosides clear into endolymph down the electrochemical gradient, presumptively via permeation of hemi-channels, facilitated glucose transporters (GLUT), electrogenic symporters, and at least two TRP channels, TRPV1 and TRPV4. Schematic diagram not to relative scale.