一种新型地塞米松制剂单次给药对脂多糖诱导的耳部损伤的保护作用

Silvia Murillo-Cuesta, Ester Lara, Jose M. Bermúdez-Muñoz, Elena Torres-Campos, Lourdes Rodríguez-de la Rosa, Pilar López-Larrubia, Signe R. Erickson, Isabel Varela-Nieto
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Methods We used a rat model of LPS-induced injury to define the functional, cellular and molecular mechanisms associated to BLB dysfunction and the protection by SPT-2101. Hearing was assessed by auditory brainstem response (ABR) recording, BLB permeability by gadolinium dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and Evans blue extravasation. Gross cochlear histology and cellular alterations were studied by hematoxylin-eosin staining and immunofluorescence. RT-qPCR, PCR array and western blotting were used to assess transcriptional and protein changes. Results LPS-challenged rats showed BLB breakdown and altered permeability as shown by the progressive increase in cochlear gadolinium uptake and Evans blue incorporation. 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引用次数: 0

摘要

血液迷宫屏障(BLB)将内耳与血液循环隔离开来,对于维持离子稳态和限制有害物质的进入至关重要。BLB的完整性被细菌脂多糖(LPS)破坏,引起内耳强烈的炎症反应,导致不可逆的耳部损伤。长期给予全身皮质类固醇是可用的治疗方法,但它显示出有限的疗效和主要的不良反应。SPT-2101是一种新颖的地塞米松原位凝胶制剂,允许单次腔内给药后缓慢和持续释放药物。方法采用lps诱导的大鼠损伤模型,明确与BLB功能障碍相关的功能、细胞和分子机制以及SPT-2101的保护作用。采用听觉脑干反应(ABR)记录评估听力,采用钆动态增强磁共振成像(DCE-MRI)评估BLB通透性和Evans蓝外渗。苏木精-伊红染色和免疫荧光法观察耳蜗大体组织学和细胞变化。RT-qPCR、PCR阵列和western blotting检测转录和蛋白变化。结果lps刺激大鼠BLB击穿、通透性改变,表现为耳蜗钆摄取和埃文斯蓝掺入逐渐增加。LPS处理增加了耳蜗中LPS toll样受体Tlr2和共受体Cd14、促炎细胞因子和受体Il1b和ll1r1以及氧化应激和炎症小体介质NRF2和NLRP3的表达。LPS还增加了外侧壁和螺旋神经节内iba1阳性巨噬细胞的浸润。单次鼓腔内注射SPT-2101可保护BLB完整性,防止耳部损伤。反复给药系统性地塞米松也有类似的效果,但单次给药没有。SPT-2101使分子炎症介质正常化,抑制巨噬细胞浸润。结论:单次局部给药地塞米松(SPT-2101)可保护内毒素血症期间BLB功能的完整性,为治疗与BLB功能障碍相关的疾病提供了新的治疗机会。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Protection of lipopolysaccharide-induced otic injury by a single dose administration of a novel dexamethasone formulation
Abstract Background The blood-labyrinth barrier (BLB) separates the inner ear from the circulation and is critical for maintaining ionic homeostasis and limiting the entry of deleterious agents. BLB integrity is disrupted by bacterial lipopolysaccharide (LPS), which elicits a strong inflammatory response in the inner ear leading to irreversible otic damage. Prolonged administration of systemic corticosteroids is the available treatment, but it shows both limited efficacy and major adverse effects. SPT-2101 is a novel in situ-forming gel formulation of dexamethasone allowing slow and sustained drug release after single intratympanic administration. Methods We used a rat model of LPS-induced injury to define the functional, cellular and molecular mechanisms associated to BLB dysfunction and the protection by SPT-2101. Hearing was assessed by auditory brainstem response (ABR) recording, BLB permeability by gadolinium dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and Evans blue extravasation. Gross cochlear histology and cellular alterations were studied by hematoxylin-eosin staining and immunofluorescence. RT-qPCR, PCR array and western blotting were used to assess transcriptional and protein changes. Results LPS-challenged rats showed BLB breakdown and altered permeability as shown by the progressive increase in cochlear gadolinium uptake and Evans blue incorporation. LPS administration increased the cochlear expression of the LPS toll-like receptors Tlr2 and co-receptor Cd14 , pro-inflammatory cytokines and receptors such as Il1b and ll1r1 , and also the oxidative stress and inflammasome mediators NRF2 and NLRP3. LPS also increased IBA1-positive macrophage infiltration in the lateral wall and spiral ganglion. A single intratympanic injection of SPT-2101 protected BLB integrity and prevented otic injury. Comparable effects were obtained by repeated administration of systemic dexamethasone, but not by a single dose. SPT-2101 administration normalized molecular inflammatory mediators and suppressed macrophage infiltration. Conclusions Our data indicate that single local administration of dexamethasone formulated as SPT-2101 protects BLB functional integrity during endotoxemia, providing a novel therapeutic opportunity to treat diseases related to BLB dysfunction.
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