The disruption and hyperpermeability of blood-labyrinth barrier mediates cisplatin-induced ototoxicity

Jiayi Gu; Ling Tong; Xin Lin; Yuming Chen; Hao Wu; Xueling Wang; Dehong Yu

doi:10.1016/j.toxlet.2021.10.015

The disruption and hyperpermeability of blood-labyrinth barrier mediates cisplatin-induced ototoxicity

Toxicol Lett. 2022 Jan 1:354:56-64. doi: 10.1016/j.toxlet.2021.10.015. Epub 2021 Oct 29.

Authors

Jiayi Gu¹, Ling Tong¹, Xin Lin², Yuming Chen¹, Hao Wu³, Xueling Wang⁴, Dehong Yu⁵

Affiliations

¹ Department of Otolaryngology-Head and Neck Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, China.
² Zhongshan Hospital, Fudan University, Shanghai, China.
³ Department of Otolaryngology-Head and Neck Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, China. Electronic address: wuhao@shsmu.edu.cn.
⁴ Department of Otolaryngology-Head and Neck Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, China. Electronic address: xuelingwang2013@163.com.
⁵ Department of Otolaryngology-Head and Neck Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, China. Electronic address: dehongyu@126.com.

PMID: 34757176
DOI: 10.1016/j.toxlet.2021.10.015

Abstract

The ototoxic mechanisms of cisplatin on the organ of Corti and spiral ganglion neurons have been extensively studied, while few studies have been focused on the stria vascularis (SV). Herein, we verified the functional and morphological impairment in SV induced by a single injection of cisplatin (12 mg/kg, I.P.), represented by a reduction in Endocochlear Potentials (EP) and strial atrophy, and explored underlying mechanisms. Our results revealed increased extravasation of chromatic tracers (Evans blue dye and FITC-dextran) around microvessels after cisplatin exposure. The increased vascular permeability could be attributed to changes of pericytes (PCs) and perivascular-resident macrophage-like melanocytes (PVM/Ms) in number or morphology, as well as the enhanced level of HIF-1α and downstream VEGF. This capillary leakage led to a high accumulation of cisplatin in the perivascular space in SV, and disrupted the integrity of blood-labyrinth barrier (BLB). Also, tight junction (ZO-1) loosening and Na⁺, K⁺-ATPase damage was considered to be other critical contributors of BLB breakdown, which resulted in EP drop and consequent hearing loss. This study explored the role of stria vascularis in cisplatin-induced ototoxicity in terms of BLB hyperpermeability and pointed to a novel therapeutic target for the prevention of cisplatin-related hearing loss.

Keywords: Blood-labyrinth barrier; Cisplatin-induced ototoxicity; Hyperpermeability; Stria vascularis.

MeSH terms

Animals
Antineoplastic Agents / toxicity*
Cisplatin / toxicity*
Cochlea / blood supply*
Cochlea / drug effects*
Disease Models, Animal
Male
Mice
Ototoxicity / etiology*
Permeability / drug effects*
Stria Vascularis / drug effects*

Substances

Antineoplastic Agents
Cisplatin