Department of Otolaryngology, Washington University, 660 South Euclid Avenue, Campus Box 8115, St. Louis, MO 63110, United States.
Hear Res. 2011 Feb;272(1-2):108-16. doi: 10.1016/j.heares.2010.10.011. Epub 2010 Oct 31.
Combinations of aminoglycosides and loop diuretics have been known to have a synergistic effect in ototoxic injury. Because murine hair cells are relatively resistant to ototoxicity compared to those of other mammals, investigators have turned to combination therapies to create ototoxic lesions in the mouse inner ear. In this paper, we perform a systematic comparison of hearing thresholds, hair cell damage and monocyte migration into the mouse cochlea after kanamycin versus combined kanamycin/furosemide and explore the pathophysiology of enhanced hair cell loss in aminoglycoside ototoxicity in the presence of loop diuretic. Combined kanamycin-furosemide resulted in elevation of threshold not only in the high frequencies, but across all frequencies with more extensive loss of outer hair cells when compared to kanamycin alone. The stria vascularis was severely atrophied and stellate cells in the spiral limbus were missing in kanamycin-furosemide exposed mice while these changes were not observed in mice receiving kanamycin alone. Monocytes and macrophages were recruited in large numbers to the spiral ligament and spiral ganglion in these mice. Combination therapy resulted in a greater number of macrophages in total, and many more macrophages were present further apically when compared to mice given kanamycin alone. Combined kanamycin-furosemide provides an effective method of addressing the relative resistance to ototoxicity that is observed in most mouse strains. As the mouse becomes increasingly more common in studies of hearing loss, and combination therapies gain popularity, recognition of the overall effects of combined aminoglycoside-loop diuretic therapy will be critical to interpretation of the interventions that follow.
氨基糖苷类抗生素和髓袢利尿剂联合使用已被证明在耳毒性损伤中有协同作用。由于与其他哺乳动物相比，鼠类毛细胞对耳毒性相对具有抗性，因此研究人员转向联合治疗方法，以在小鼠内耳中产生耳毒性病变。在本文中，我们对卡那霉素与卡那霉素/呋塞米联合使用后对小鼠内耳的听力阈值、毛细胞损伤和单核细胞迁移进行了系统比较，并探讨了在存在髓袢利尿剂的情况下，氨基糖苷类耳毒性中毛细胞丢失增强的病理生理学机制。与单独使用卡那霉素相比，联合使用卡那霉素和呋塞米不仅在高频范围内，而且在所有频率范围内都导致阈值升高，并且外毛细胞的损失更为广泛。血管纹严重萎缩，螺旋边缘的星形细胞缺失，而在单独使用卡那霉素的小鼠中未观察到这些变化。在这些小鼠中，大量单核细胞和巨噬细胞被募集到螺旋韧带和螺旋神经节。与单独使用卡那霉素的小鼠相比，联合治疗导致总巨噬细胞数量增加，并且在更靠近顶部的部位存在更多的巨噬细胞。联合使用卡那霉素和呋塞米为解决大多数小鼠品系中观察到的相对耳毒性抗性提供了有效方法。随着小鼠在听力损失研究中变得越来越普遍，并且联合治疗方法越来越受欢迎，认识到联合使用氨基糖苷类抗生素和髓袢利尿剂治疗的整体效果对于解释后续干预措施至关重要。
