Infection-Mediated Vasoactive Peptides Modulate Cochlear Uptake of Fluorescent Gentamicin

Koo, Ja Won; Wang, Qi; Steyger, Peter S.

doi:10.1159/000322851

Cited by 18 publications

(22 citation statements)

References 68 publications

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“…The cytoplasmic intensity of GTTR fluorescence is dose-dependent, unlike gentamicin immunofluorescence where the greater abundance of epitope binding sites can overwhelm the number of available antibodies (13, 20). Thus, changes in cochlear uptake of aminoglycosides can be quantitatively assayed using GTTR and confocal microscopy (13, 17, 20, 23). …”

Section: Resultsmentioning

confidence: 99%

“…We previously reported that two inflammatory-mediated vasoactive peptides – histamine and serotonin – can modulate cochlear uptake of GTTR (17). Twenty-four hours after LPS injection, serum histamine concentrations were not modulated, while serum serotonin concentrations were significantly decreased in a dose-dependent manner in LPS-treated mice (Table 2, fig.…”

Section: Resultsmentioning

confidence: 99%

“…Vasoactive peptides also modulate cochlear uptake of gentamicin across the BLB (17). However, most studies of ototoxicity involve healthy preclinical models, and the effect of induced systemic inflammation on ototoxicity has only recently been reported (18).…”

Section: Introductionmentioning

confidence: 99%

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Endotoxemia-mediated inflammation potentiates aminoglycoside-induced ototoxicity

Koo

Quintanilla‐Dieck²,

Jiang³

et al. 2015

Sci. Transl. Med.

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130

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The ototoxic aminoglycoside antibiotics are essential to treat severe bacterial infections, particularly in neonatal intensive care units. Using a bacterial lipopolysaccharide (LPS) experimental model of sepsis, we tested whether LPS-mediated inflammation potentiates cochlear uptake of aminoglycosides and permanent hearing loss in mice. Using confocal microscopy and enzyme-linked immunosorbent assays, we found that low-dose LPS (endotoxemia) greatly increased cochlear concentrations of aminoglycosides and resulted in vasodilation of cochlear capillaries without inducing paracellular flux across the blood-labyrinth barrier (BLB), or elevating serum concentrations of the drug. Additionally, endotoxemia increased expression of both serum and cochlear inflammatory markers. These LPS-induced changes, classically mediated by Toll-like Receptor 4 (TLR4), were attenuated in TLR4-hyporesponsive mice. Multiday dosing with aminoglycosides during chronic endotoxemia induced greater hearing threshold shifts and sensory cell loss compared to mice without endotoxemia. Thus, endotoxemia-mediated inflammation enhanced aminoglycoside trafficking across the BLB, and potentiated aminoglycoside-induced ototoxicity. These data indicate that patients with severe infections are at greater risk of aminoglycoside-induced hearing loss than previously recognized.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Endotoxemia-mediated inflammation potentiates aminoglycoside-induced ototoxicity

Koo

Quintanilla‐Dieck²,

Jiang³

et al. 2015

Sci. Transl. Med.

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130

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“…This is further evidenced by the enhanced drug uptake and significantly increased hearing damage when the barrier is disrupted by diuretics or noise exposure (Ding et al, 2007; Li et al, 2015). Vasoactive peptides also augment cochlear uptake of ototoxic drugs such as gentamicin (Koo et al, 2011). The pathway of drug uptake from the stria vascularis is found to involve transporter systems as well as channels, including transient receptor potential cation channel subfamily V member 4 (TRPV4) in strial capillaries (Ishibashi et al, 2009; Karasawa et al, 2008).…”

Section: Intrastrial Fluid-blood Barrier and Hearing Disordersmentioning

confidence: 99%

Pathophysiology of the cochlear intrastrial fluid-blood barrier (review)

2016

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The blood-labyrinth barrier (BLB) in the stria vascularis is a highly specialized capillary network that controls exchanges between blood and the intrastitial space in the cochlea. The barrier shields the inner ear from blood-born toxic substances and selectively passes ions, fluids, and nutrients to the cochlea, playing an essential role in the maintenance of cochlear homeostasis. Anatomically, the BLB is comprised of endothelial cells (ECs) in the strial microvasculature, elaborated tight and adherens junctions, pericytes (PCs), basement membrane (BM), and perivascular resident macrophage-like melanocytes (PVM/Ms), which together form a complex “cochlear-vascular unit” in the stria vascularis. Physical interactions between the ECs, PCs, and PVM/Ms, as well as signaling between the cells, is critical for controlling vascular permeability and providing a proper environment for hearing function. Breakdown of normal interactions between components of the BLB is seen in a wide range of pathological conditions, including genetic defects and conditions engendered by inflammation, loud sound trauma, and ageing. In this review, we will discuss prevailing views of the structure and function of the strial cochlear-vascular unit (also referred to as the “intrastrial fluid-blood barrier”). We will also discuss the disrupted homeostasis seen in a variety of hearing disorders. Therapeutic targeting of the strial barrier may offer opportunities for improvement of hearing health and amelioration of auditory disorders.

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“…Exposure to intravenous aminoglycoside antibiotics like gentamicin in the NICU may contribute up to 25% of this unexplained rate of hearing loss [5]. Experimental models of systemic inflammation show increased cochlear uptake of gentamicin into the cochlea and exacerbation of ototoxicity [6, 7]. This ototoxic synergy between gentamicin exposure and systemic inflammation may also contribute to the higher rates of hearing loss observed in NICU subjects.…”

Section: 1 Introductionmentioning

confidence: 99%

Effect of sepsis and systemic inflammatory response syndrome on neonatal hearing screening outcomes following gentamicin exposure

Cross

Liao

Urdang

et al. 2015

International Journal of Pediatric Otorhinolaryngology

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Rationale Hearing loss in neonatal intensive care unit (NICU) graduates range from 2–15% compared to 0.3% in full-term births, and the etiology of this discrepancy remains unknown. The majority of NICU admissions receive potentially ototoxic aminoglycoside therapy, such as gentamicin, for presumed sepsis. Endotoxemia and inflammation are associated with increased cochlear uptake of aminoglycosides and potentiated ototoxicity in mice. We tested the hypothesis that sepsis or systemic inflammatory response syndrome (SIRS) and intravenous gentamicin exposure increases the risk of hearing loss in NICU admissions. Methods The Institutional Review Board at Oregon Health & Science University (OHSU) approved this study design. Two hundred and eight infants met initial criteria, and written, informed consent were obtained from parents or guardians of 103 subjects ultimately enrolled in this study. Prospective data from 91 of the enrolled subjects at OHSU Doernbecher Children’s Hospital Neonatal Care Center were processed. Distortion product otoacoustic emissions (DPOAEs; f2 frequency range: 2,063 to 10,031 Hz) were obtained prior to discharge to assess auditory performance. To pass the DPOAE screen, normal responses in >6 of 10 frequencies in both ears were required; otherwise the subject was considered a “referral” for a diagnostic hearing evaluation after discharge. Cumulative dosing data and diagnosis of neonatal sepsis or SIRS were obtained from OHSU’s electronic health record system, and the data processed to obtain risk ratios. Results Using these DPOAE screening criteria, 36 (39.5%) subjects would be referred. Seventy-four (81%) subjects had intravenous gentamicin exposure. Twenty (22%) had ≥4 days of gentamicin, and 71 (78%) had <4 days. The risk ratio (RR) of referral with ≥4 days of gentamicin was 1.92 (p=0.01). Eighteen subjects had sepsis or met neonatal SIRS criteria, 9 of whom had ≥5 days of gentamicin and a DPOAE referral risk ratio of 2.12 (p=0.02) compared to all other subjects. Combining subjects with either vancomycin or furosemide overlap with gentamicin treatment yielded an almost significant risk ratio (RR = 1.77, p=0.05) compared to the rest of the cohort. Conclusions We report an increased risk of referral with DPOAE screening for those receiving ≥4 days of intravenous gentamicin administration that may contribute to the greater prevalence of hearing loss in NICU graduates. We propose an expanded prospective study to gather a larger cohort of subjects, identifying those with sepsis or neonatal SIRS, to increase the statistical power of this study design. Subsequent studies also need to obtain follow-up diagnostic audiological data to verify whether the outcomes of DPOAE screening, in addition to the standard AABR screen, is a reliable predictor of permanent hearing loss following gentamicin exposure in the NICU.

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Infection-Mediated Vasoactive Peptides Modulate Cochlear Uptake of Fluorescent Gentamicin

Cited by 18 publications

References 68 publications

Endotoxemia-mediated inflammation potentiates aminoglycoside-induced ototoxicity

Endotoxemia-mediated inflammation potentiates aminoglycoside-induced ototoxicity

Pathophysiology of the cochlear intrastrial fluid-blood barrier (review)

Effect of sepsis and systemic inflammatory response syndrome on neonatal hearing screening outcomes following gentamicin exposure

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