Neutrophil and Toll-Like Receptor 4 Contributions to Endotoxemia-Enhanced Gentamicin Ototoxicity

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 DESCRIPTION (provided by applicant): Sepsis occurs when serious bacterial infection (e.g. meningitis, endocarditis, peritonitis; usually including bacteremia) induces Systemic Inflammatory Response Syndrome (SIRS). Aminoglycosides are an essential class of antibiotics reserved for these life-threatening infections. Yet, despite their bactericidal efficacy, aminoglycosides can also induce life-long hearing loss and vestibular deficits, affecting quality of life indicators, e.g., listening and language skills, educational attainment. Recent evidence suggests that experimentally- induced SIRS, with bacterial lipopolysaccharide (LPS), enhances cochlear loading of aminoglycosides, potentiating the ototoxic side-effects of these drugs. This coincides with increased cochlear levels of pro- inflammatory molecules (such as cytokines and chemokines) at the mRNA and protein levels. Furthermore, cochlear levels of aminoglycosides and pro-inflammatory cytokines are reduced in mice with dysfunctional TLR4 (the primary receptor for LPS). Together, these pilot data suggest that TLR4-mediated inflammation in the cochlea is responsible for enhancing cochlear levels of aminoglycosides and pro-inflammatory cytokines. Patients with neutropenia, especially neonates and patients treated with chemotherapy, are exceptionally vulnerable to sepsis. During sepsis, the primary role of neutrophils is to eliminate bacteria, but during SIRS, this can also induce collateral neutrophil-mediated vascular injury in non-infected tissues, causing much of the morbidity and mortality associated with sepsis. The overall hypothesis of this proposal is that SIRS dysregulates the blood-labyrinth barrier of the cochlea via the innate immune response, increasing cochlear uptake of aminoglycosides and subsequent ototoxicity. The proposed experiments will (i) measure cochlear inflammatory marker levels during SIRS in TLR4- and neutrophil-deficient mice over time; (ii) characterize the cochlear innate immune response during SIRS with a focus on neutrophils; and (iii) Characterize how the cochlear inflammatory response perturbs blood-labyrinth barrier physiology potentiating aminoglycoside- induced ototoxicity. These data will allow us to determine the relative contributions of immune-response molecular mediators and neutrophils to SIRS-enhanced cochlear aminoglycoside loading. The data from the proposed studies will be relevant to clinical use of aminoglycosides in the management of sepsis, by characterizing which factors increase the risk of aminoglycoside-induced ototoxicity. Stronger, evidence-based definition of the indications and contraindications for aminoglycoside therapy will reduce the prevalence and degree of the life-long ototoxicity associated with aminoglycosides.