黏多糖贮积症 I 型小鼠耳部与年龄相关的功能和组织病理学变化。
Age-related functional and histopathological changes of the ear in the MPS I mouse.
作者信息
Schachern Patricia A, Cureoglu Sebahattin, Tsuprun Vladimir, Paparella Michael M, Whitley Chester B
机构信息
Department of Otolaryngology, Otitis Media Research Center, University of Minnesota, Minneapolis, MN, USA.
出版信息
Int J Pediatr Otorhinolaryngol. 2007 Feb;71(2):197-203. doi: 10.1016/j.ijporl.2006.09.016. Epub 2006 Nov 13.
OBJECTIVE
Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disorder caused by a mutation in the gene encoding the enzyme alpha-L-iduronidase. This enzyme is responsible for degradation of dermatan and heparan sulfates. Enzyme deficiency results in their accumulation in lysosomes of virtually all organs, resulting in severe somatic and neurological changes. Clinical findings of otitis media with mixed hearing loss are common. Cellular and molecular mechanisms of ear pathology and hearing loss are not understood. The purpose of this study is to describe the age-related audiologic and histopathologic changes of the ear in the mouse model of MPS I.
METHODS
Auditory brainstem responses (ABR) were obtained to clicks and tone bursts at 1-32kHz, and pathological changes to middle and inner ears were studied with light and electron microscopy in 53 mice that included: (1) wild type (+/+)-five at 2 months, five at 4-6 months, and five at 13-19 months; (2) heterozygotes (+/-)-four at 2 months, five at 4-6 months, and eight at 13-19 months; and (3) homozygotes (-/-)-five at 2 months, six at 4-6 months, and five at 13-19 months. Histopathology was also done on five newborn -/- mice.
RESULTS
In newborns, no lysosomal storage was observed and the ear appeared age appropriately normal. In all other -/- mice, cells with lysosomal storage vacuoles were observed in spiral ligament, spiral prominence, spiral limbus, basilar membrane, epithelial and mesothelial cells of Reissner's membrane, endothelial cells of vessels, and some ganglion cells; their number increased with aging. Hair cell loss was not observed at 2 or 6 months, but there was total loss of the organ of Corti in year-old mice. Hearing of -/- mice was significantly decreased at all ages compared to +/+ and +/-. Hearing loss progressed from mild to moderate loss at 2 months to profound at 6 months and total deafness by 1 year of age.
CONCLUSIONS
Progressive age-related changes suggest early therapeutic intervention to prevent sensory cell damage and hearing loss.
目的
I型黏多糖贮积症（MPS I）是一种常染色体隐性疾病，由编码α-L-艾杜糖醛酸酶的基因突变引起。该酶负责降解硫酸皮肤素和硫酸乙酰肝素。酶缺乏导致它们在几乎所有器官的溶酶体中蓄积，从而引起严重的躯体和神经学改变。伴有混合性听力损失的中耳炎的临床发现很常见。耳部病理学和听力损失的细胞及分子机制尚不清楚。本研究的目的是描述I型黏多糖贮积症小鼠模型中耳部与年龄相关的听力学和组织病理学变化。
方法
对53只小鼠进行了听觉脑干反应（ABR）测试，以记录1-32kHz的短声和短纯音反应，并采用光镜和电镜研究中耳和内耳的病理变化。这些小鼠包括：（1）野生型（+/+）——2月龄5只、4-6月龄5只、13-19月龄5只；（2）杂合子（+/-）——2月龄4只、4-6月龄5只、13-19月龄8只；（3）纯合子（-/-）——2月龄5只、4-6月龄6只、13-19月龄5只。还对5只新生的-/-小鼠进行了组织病理学检查。
结果
在新生小鼠中，未观察到溶酶体贮积，耳部外观在年龄上适当正常。在所有其他-/-小鼠中，在螺旋韧带、螺旋凸、螺旋缘、基底膜、Reissner膜的上皮和间皮细胞、血管内皮细胞以及一些神经节细胞中观察到有溶酶体贮积空泡的细胞；其数量随年龄增加。在2个月或6个月时未观察到毛细胞丢失，但在1岁小鼠中柯蒂器完全缺失。与+/+和+/-小鼠相比，-/-小鼠在所有年龄段的听力均显著下降。听力损失从2个月时的轻度至中度进展为6个月时的重度，并在1岁时完全失聪。
结论
与年龄相关的渐进性变化提示应尽早进行治疗干预，以防止感觉细胞损伤和听力损失。
Zotero 插件