Activation of Lipopolysaccharide–TLR4 Signaling Accelerates the Ototoxic Potential of Cisplatin in Mice

Abstract

Dysfunction in immune surveillance during anticancer chemotherapy of patients often causes weakness of the host defense system and a subsequent increase in microbial infections. However, the deterioration of organ-specific function related to microbial challenges in cisplatin-treated patients has not yet been elucidated. In this study, we investigated cisplatin-induced TLR4 expression and its binding to LPS in mouse cochlear tissues and the effect of this interaction on hearing function. Cisplatin increased the transcriptional and translational expression of TLR4 in the cochlear tissues, organ of Corti explants, and HEI-OC1 cells. Furthermore, cisplatin increased the interaction between TLR4 and its microbial ligand LPS, thereby upregulating the production of proinflammatory cytokines, such as TNF-α, IL-1β, and IL-6, via NF-κB activation. In C57BL/6 mice, the combined injection of cisplatin and LPS caused severe hearing impairment compared with that in the control, cisplatin-alone, or LPS-alone groups, whereas this hearing dysfunction was completely suppressed in both TLR4 mutant and knockout mice. These results suggest that hearing function can be easily damaged by increased TLR expression and microbial infections due to the weakened host defense systems of cancer patients receiving therapy comprising three to six cycles of cisplatin alone or cisplatin combined with other chemotherapeutic agents. Moreover, such damage can occur even though patients may not experience ototoxic levels of cumulative cisplatin concentration.

Endotoxemia-mediated inflammation potentiates aminoglycoside-induced ototoxicity

“…These data support prior observations that bacteremia and hyperthermia (an experimental model for sepsis-induced fever) enhanced aminoglycoside-induced ototoxicity in humans and mice, respectively (78, 79). Endotoxemia also potentiated aminoglycoside-induced nephrotoxicity (80), and heightened the degree of cisplatin-induced PTS (81). …”

An integrated view of cisplatin-induced nephrotoxicity and ototoxicity

“…Systemic inflammation can exacerbate cochlear uptake of ototoxic drugs and potentiate cisplatin-induced ototoxicity (Koo et al, 2015; Oh et al, 2011). Thus, radiation therapy that kills commensal bacteria could inadvertently induce systemic inflammation and potentiate cisplatin-induced ototoxicity during combination anti-neoplastic therapies.…”

Protective mechanism of Korean Red Ginseng in cisplatin-induced ototoxicity through attenuation of nuclear factor-κB and caspase-1 activation

“…Accumulating evidence has indicated that pro-inflammatory cytokines may be involved in cochlear damage (6)(7)(8)(9)(10). These cytokines were shown to induce secondary inflammatory responses, including leukocyte infiltration and scar formation.…”