Hirose Keiko, Li Song-Zhe
Department of Otolaryngology, Washington University School of Medicine, St. Louis, Missouri, USA.
Department of Otolaryngology, Washington University School of Medicine, St. Louis, Missouri, USA.
Hear Res. 2019 Mar 15;374:49-57. doi: 10.1016/j.heares.2019.01.006. Epub 2019 Jan 20.
The blood-perilymph barrier serves a critical role by separating the components of blood from inner ear fluids, limiting traffic of cells, proteins and other solutes into the labyrinth, and allowing gas (O-CO) exchange. Inflammation produces changes in the blood-perilymph barrier resulting in increased vascular permeability. It is commonly thought that compromise of the blood-inner ear barrier would lead to hearing impairment through loss of the endocochlear potential (EP). In fact, the effect of increasing cochlear vascular permeability on hearing function and EP is poorly understood. We used a novel method to measure the integrity of the blood-perilymph barrier and demonstrated the effects of barrier compromise on ABR threshold and EP. We also investigated the contribution of CX3CR1 cochlear macrophages and CCR2 inflammatory monocytes to barrier function after systemic exposure to lipopolysaccharide (LPS). We found that systemic LPS induced a profound change in vascular permeability, which correlated with minimal change in ABR threshold and EP. Macrophage depletion using CX3CR1-DTR mice did not alter the baseline permeability of cochlear vessels and resulted in preservation of barrier function in LPS-treated animals. We conclude that cochlear macrophages are not required to maintain the barrier in normal mice and activated macrophages are a critical factor in breakdown of the barrier after LPS. CCR2 null mice demonstrated that LPS induction of barrier leakiness occurs in the absence of CCR2 expression. Thus, enhanced aminoglycoside ototoxicity after LPS can be linked to the expression of CCR2 in inflammatory monocytes, and not to preservation of the blood-perilymph barrier in CCR2 knockout mice.
血-外淋巴屏障通过将血液成分与内耳液分隔开来，限制细胞、蛋白质和其他溶质进入迷路，并允许气体（氧气-二氧化碳）交换，发挥着关键作用。炎症会导致血-外淋巴屏障发生变化，从而增加血管通透性。人们普遍认为，血-内耳屏障受损会导致内淋巴电位（EP）丧失，进而导致听力障碍。事实上，耳蜗血管通透性增加对听力功能和EP的影响尚不清楚。我们采用一种新方法来测量血-外淋巴屏障的完整性，并证明了屏障受损对听性脑干反应（ABR）阈值和EP的影响。我们还研究了全身暴露于脂多糖（LPS）后，CX3CR1耳蜗巨噬细胞和CCR2炎性单核细胞对屏障功能的作用。我们发现，全身注射LPS会引起血管通透性的显著变化，这与ABR阈值和EP的微小变化相关。使用CX3CR1-DTR小鼠清除巨噬细胞并未改变耳蜗血管的基线通透性，且在LPS处理的动物中维持了屏障功能。我们得出结论，正常小鼠维持屏障功能不需要耳蜗巨噬细胞，而活化的巨噬细胞是LPS处理后屏障破坏的关键因素。CCR2基因敲除小鼠表明，LPS诱导的屏障渗漏在缺乏CCR2表达的情况下也会发生。因此，LPS后氨基糖苷类耳毒性增强可能与炎性单核细胞中CCR2的表达有关，而与CCR2基因敲除小鼠中血-外淋巴屏障的维持无关。
