Cisplatin-Induced Stria Vascularis Damage Is Associated with Inflammation and Fibrosis

Abstract

The stria vascularis (SV) generates the endocochlear potential (EP) in the inner ear and is necessary for proper hair cell (HC) mechanotransduction and hearing. Cell junctions are indispensable for the establishment of compositionally distinct fluid compartments in the inner ear. Ototoxic drug cisplatin can damage SV and cause sensorineural hearing loss; however, the underlying mechanisms behind such injury are unclear. In this study, after the intraperitoneal injection of cisplatin (3 mg/kg/day for 7 days) in mice, we determined the auditory function by EP recording and auditory brainstem response (ABR) analysis, observed the ultrastructure of SV by transmission electron microscopy (TEM), and examined the expression and distribution of cell junction proteins by western blot, PCR, and immunofluorescence staining. We discovered that the EP was significantly reduced while ABR thresholds were significantly elevated in cisplatin-treated mice; cisplatin induced ultrastructural changes in marginal cells (MCs), endothelial cells (ECs), pericytes, etc. We found that cisplatin insulted auditory function not only by reducing the expression of zonula occludens protein-1 (ZO-1) in MCs of the SV but also by decreasing the expression of connexin 26 (Cx26) and connexin 43 (Cx43) in MCs and basal cells (BCs). More importantly, cisplatin induced activations of perivascular-resident macrophage-like melanocytes (PVM/Ms) and interleukin-1beta (IL-1β) as well as increased expressions of profibrotic proteins such as laminin and collagen IV in SV. Thus, our results firstly showed that cisplatin induced fibrosis, inflammation, and the complex expression change of cell junctions in SV.

Bidirectional Transport of IgE by CD23 in the Inner Ear of Patients with Meniere’s Disease

“…Extraction of mRNA and quantitative real-time PCR Total RNA was extracted using an RNA extraction kit (RNeasy Mini QIAcube kit, QIAGEN, Hilden, Germany) from PBMCs, HEI-OC1 cells, and tissues samples. Relative expression of target genes was measured by quantitative real-time PCR (qRT-PCR) that was performed using an Eppendorf AG 22331 PCR machine (Eppendorf, Hamburg, Germany), as reported earlier (26). Briefly, qRT-PCR was performed using SYBR Green Premix Ex Taq (RR42LR, Takara Biotechnology, Shiga, Japan), and GAPDH was used as the housekeeping gene.…”

“…Briefly, qRT-PCR was performed using SYBR Green Premix Ex Taq (RR42LR, Takara Biotechnology, Shiga, Japan), and GAPDH was used as the housekeeping gene. Fold-change differences in mRNA expression were determined using the comparative cycle threshold method (26). The primers for house mice and humans used in this experiment are listed in Table I.…”

Role of the Stria Vascularis in the Pathogenesis of Sensorineural Hearing Loss: A Narrative Review

“…Recently, the role of inflammation in drug-induced hearing loss has also gained attention. Zhang et al (2020) found that cisplatin induced the secretion of IL-1 β in SV, suggesting that inflammation is involved in the process of cisplatin-induced SV damage.…”

Building inner ears: recent advances and future challenges for in vitro organoid systems

“…Thus, the potential disease modeling applications are limited. For instance, there are cochlear and vestibular diseases, as well as certain ototoxic agents, that have their pathological impact—either directly or indirectly—on non-sensory cells of the inner ear [ 4 , 75 , 82 – 85 ]. Therefore, it will be essential to generate inner ear models that contain a diverse functional unit of inner ear cell types to capture complex genetic or drug-related mechanisms.…”