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Paraquat initially damages cochlear support cells leading to anoikis-like hair cell death.

ABSTRACT: Paraquat (PQ), one of the most widely used herbicides, is extremely dangerous because it generates the highly toxic superoxide radical. When paraquat was applied to cochlear organotypic cultures, it not only damaged the outer hair cells (OHCs) and inner hair cells (IHCs), but also caused dislocation of the hair cell rows. We hypothesized that the dislocation arose from damage to the support cells (SCs) that anchors hair cells within the epithelium. To test this hypothesis, rat postnatal cochlear cultures were treated with PQ. Shortly after PQ treatment, the rows of OHCs separated from one another and migrated radially away from IHCs suggesting loss of cell-cell adhesion that hold the hair cells in proper alignment. Hair cells dislocation was associated with extensive loss of SCs in the organ of Corti, loss of tympanic border cells (TBCs) beneath the basilar membrane, the early appearance of superoxide staining and caspase-8 labeling in SCs below the OHCs and disintegration of E-cadherin and ?-catenin in the organ of Corti. Damage to the TBCs and SCs occurred prior to loss of OHC or IHC loss suggesting a form of detachment-induced apoptosis referred to as anoikis.

SUBMITTER: Zhang J

PROVIDER: S-EPMC5984146 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Paraquat initially damages cochlear support cells leading to anoikis-like hair cell death.

Zhang Jianhui J Sun Hong H Salvi Richard R Ding Dalian D

Hearing research 20180313

Paraquat (PQ), one of the most widely used herbicides, is extremely dangerous because it generates the highly toxic superoxide radical. When paraquat was applied to cochlear organotypic cultures, it not only damaged the outer hair cells (OHCs) and inner hair cells (IHCs), but also caused dislocation of the hair cell rows. We hypothesized that the dislocation arose from damage to the support cells (SCs) that anchors hair cells within the epithelium. To test this hypothesis, rat postnatal cochlear ...[more]

PMID: 29563067

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Project description:Noise-induced hearing loss has gained relevance as one of the most common forms of hearing impairment. The anatomical correlates of hearing loss, principally cell damage and/or death, are relatively well-understood histologically. However, much less is known about the physiological aspects of damaged, surviving cells. Here we addressed the functional consequences of noise exposure on the capacity of inner hair cells (IHCs) to release synaptic vesicles at synapses with spiral ganglion neurons (SGNs). Mice of either sex at postnatal day (P) 15-16 were exposed to 1-12 kHz noise at 120 dB sound pressure level (SPL), for 1 h. Exocytosis was measured by tracking changes in membrane capacitance (ΔCm) from IHCs of the apical cochlea. Upon IHC depolarization to different membrane potentials, ΔC m showed the typical bell-shaped curve that mirrors the voltage dependence of Ca2+ influx, in both exposed and unexposed cells. Surprisingly, from IHCs at 1-day after exposure (d.a.e.), we found potentiation of exocytosis at the peak of the bell-shaped curve. The increase in exocytosis was not accompanied by changes in whole-cell Ca2+ influx, suggesting a modification in coupling between Ca2+ channels and synaptic vesicles. Consistent with this notion, noise exposure also changed the Ca2+-dependence of exocytosis from linear to supralinear. Noise exposure did not cause loss of IHCs, but did result in a small reduction in the number of IHC-SGN synapses at 1-d.a.e. which recovered by 14-d.a.e. In contrast, a strong reduction in auditory brainstem response wave-I amplitude (representing synchronous firing of SGNs) and distortion product otoacoustic emissions (reflecting outer hair cell function) indicated a profound hearing loss at 1- and 14-d.a.e. To determine the role of glutamate release in the noise-induced potentiation of exocytosis, we evaluated vesicular glutamate transporter-3 (Vglut3) knock-out (KO) mice. Unlike WT, IHCs from Vglut3 KO mice showed a noise-induced reduction in ΔC m and Ca2+ influx with no change in the Ca2+-dependence of exocytosis. Together, these results indicate that traumatic noise exposure triggers changes of IHC synaptic function including a Vglut3-dependent potentiation of exocytosis.

Project description:BackgroundSeptic shock is often associated with acute respiratory distress syndrome, a serious clinical problem exacerbated by improper mechanical ventilation. Ventilator-induced lung injury (VILI) can exacerbate the lung injury caused by acute respiratory distress syndrome, significantly increasing the morbidity and mortality. In this study, we asked the following questions: what is the effect of the lung position (dependent lung versus nondependent lung) on the rate at which VILI occurs in the normal lung? Will positive end-expiratory pressure (PEEP) slow the progression of lung injury in either the dependent lung or the nondependent lung?Materials and methodsSprague-Dawley rats (n = 19) were placed on mechanical ventilation, and the subpleural alveolar mechanics were measured with an in vivo microscope. Animals were placed in the lateral decubitus position, left lung up to measure nondependent alveolar mechanics and left lung down to film dependent alveolar mechanics. Animals were ventilated with a high peak inspiratory pressure of 45 cmH2O and either a low PEEP of 3 cmH2O or a high PEEP of 10 cmH2O for 90 minutes. Animals were separated into four groups based on the lung position and the amount of PEEP: Group I, dependent + low PEEP (n = 5); Group II, nondependent + low PEEP (n = 4); Group III, dependent + high PEEP (n = 5); and Group IV, nondependent + high PEEP (n = 5). Hemodynamic and lung function parameters were recorded concomitant with the filming of alveolar mechanics. Histological assessment was performed at necropsy to determine the presence of lung edema.ResultsVILI occurred earliest (60 min) in Group II. Alveolar instability eventually developed in Groups I and II at 75 minutes. Alveoli in both the high PEEP groups were stable for the entire experiment. There were no significant differences in arterial PO2 or in the degree of edema measured histologically among experimental groups.ConclusionThis open-chest animal model demonstrates that the position of the normal lung (dependent or nondependent) plays a role on the rate of VILI.

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Paraquat initially damages cochlear support cells leading to anoikis-like hair cell death.

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Paraquat initially damages cochlear support cells leading to anoikis-like hair cell death.

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