Research Service, VA Loma Linda Healthcare System, Loma Linda, CA 92357, USA.
Department of Otolaryngology-Head and Neck Surgery, Loma Linda University Health, Loma Linda, CA 92354, USA.
Int J Mol Sci. 2022 Jul 1;23(13):7343. doi: 10.3390/ijms23137343.
Combining aminoglycosides and loop diuretics often serves as an effective ototoxic approach to deafen experimental animals. The treatment results in rapid hair cell loss with extended macrophage presence in the cochlea, creating a sterile inflammatory environment. Although the early recruitment of macrophages is typically neuroprotective, the delay in the resolution of macrophage activity can be a complication if the damaged cochlea is used as a model to study subsequent therapeutic strategies. Here, we applied a high dose combination of systemic gentamicin and furosemide in and mice and studied the ototoxic consequences in the cochlea, including hair cell survival, ribbon synaptic integrity, and macrophage activation up to 15-day posttreatment. The activity of macrophages in the basilar membrane was correlated to the severity of cochlear damage, particularly the hair cell damage. Comparatively, cochleae were more vulnerable to the ototoxic challenge with escalated macrophage activation. In addition, the ribbon synaptic deterioration was disproportionately limited when compared to the degree of outer hair cell loss in mice. The innate and differential otoprotection in mice appears to be associated with the rapid activation of cochlear macrophages and a certain level of synaptogenesis after the combined gentamicin and furosemide treatment.
将氨基糖苷类药物和噻嗪类利尿剂联合使用通常是使实验动物失聪的有效耳毒性方法。这种治疗方法会导致毛细胞迅速丧失，耳蜗中巨噬细胞持续存在，从而产生无菌性炎症环境。尽管巨噬细胞的早期募集通常具有神经保护作用，但如果受损的耳蜗被用作研究后续治疗策略的模型，巨噬细胞活性的延迟解决可能是一个并发症。在这里，我们在 和 小鼠中应用了系统给予庆大霉素和呋塞米的高剂量组合，并研究了耳蜗中的耳毒性后果，包括毛细胞存活、带状突触完整性和巨噬细胞激活，直至治疗后 15 天。基底膜中巨噬细胞的活性与耳蜗损伤的严重程度相关，特别是毛细胞损伤。相比之下， 耳蜗对耳毒性挑战更敏感，巨噬细胞激活加剧。此外，与 小鼠中外毛细胞丧失的程度相比，带状突触恶化不成比例地受到限制。 小鼠中先天和差异的耳保护作用似乎与联合使用庆大霉素和呋塞米治疗后耳蜗巨噬细胞的快速激活和一定程度的突触发生有关。
