Otitis Media Impact on the Inner Ear

中耳炎对内耳的影响

• 批准号: 7146763
• 负责人: DENNIS ROYAL TRUNE
• 金额: $ 23.03万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7146763
• 关键词: bacteria; cytokine; labyrinth; middle ear; otitis media; pathology

DESCRIPTION (provided by applicant): In spite of decades of study, it is still not clear how otitis media impacts the inner ear to cause sensorineural hearing loss. Thus, it is impossible to predict who is at risk or what markers can be used to determine if inner ear inflammation is occurring, making effective diagnosis and management difficult. Therefore, our bng-term goal is to identify how inflammation in the middle ear causes cochlear pathology. The PI and his colleagues, has recently developed an acute otitis media mouse model, as well as described chronic otitis media in the C3H/HeJ mouse that has a defect in its toll like receptor 4 (TLR4). These collaborations have led to the development of new methods to characterize both middle ear and inner ear cytokine expression, nuclear factor-kB (NF-kB)-mediated inflammatory processes, nitric oxide-mediated cochlear damage, and quantitative immune cell pathology. The proposed studies will capitalize on both these acute and chronic middle ear disease mouse models to establish the correlative middle ear and inner ear immune profiles. This will describe for the first time the molecular immune mechanisms by which otitis media can directly cause inner ear pathology. Therefore, this research has the potential to significantly advance our understanding of inner ear inflammatory processes elicited by both acute and chronic otitis media and lay the groundwork for development of new procedures for the detection and therapy of sensorineural hearing loss. The proposed studies will utilize BALB/c mice inoculated in the middle ear with heat-killed Haemophilous influenza or Streptococcus pneumoniae (acute otitis media) and C3H/HeJ mice defective for TLR4 (chronic otitis media) to characterize inner ear pathology, physiology, cytokine gene expression, cytokine levels, NF- kB activated inflammatory processes, and reactive oxygen species. The specific aims of this proposal are: Aim 1: To characterize the inner ear inflammatory profile in acute otitis media. This will test the hypothesis that acute otitis media causes a transient inner ear immune response characterized by Thl inflammatory processes. Aim 2: To characterize the inner ear inflammatory profile in chronic otitis media. This will test the hypothesis that chronic otitis media causes a persistent and destructive inner ear immune response characterized by expanded Th1 inflammatory processes. Inner ear pathology will be measured with auditory brainstem response audiometry, the endocochlear potential, light and electron microscopy, and immunohistochemistry of inflammatory mediators. Cochlear immune-mediated processes will be assessed by measurement of inflammatory cytokines, cytokine gene expression, and ELISA of transcription factors, vascular related factors, and reactive oxygen species.

描述（由申请人提供）：尽管经过几十年的研究，中耳炎如何影响内耳导致感音神经性听力损失仍不清楚。因此，不可能预测谁有风险，也不可能用什么标记物来确定是否发生内耳炎症，这使得有效的诊断和管理变得困难。因此，我们的长期目标是确定中耳炎症是如何引起耳蜗病理的。PI和他的同事们最近开发了一种急性中耳炎小鼠模型，并描述了C3H/HeJ小鼠的慢性中耳炎，其toll样受体4 （TLR4）存在缺陷。这些合作导致了新方法的发展，以表征中耳和内耳细胞因子表达、核因子kb （NF-kB）介导的炎症过程、一氧化氮介导的耳蜗损伤和定量免疫细胞病理学。该研究将利用这些急性和慢性中耳疾病小鼠模型来建立相关的中耳和内耳免疫谱。这将首次描述中耳炎可直接引起内耳病理的分子免疫机制。因此，这项研究有可能显著提高我们对急性和慢性中耳炎引起的内耳炎症过程的理解，并为开发检测和治疗感音神经性听力损失的新方法奠定基础。该研究将利用BALB/c小鼠在中耳接种热灭活的嗜血流感或肺炎链球菌（急性中耳炎）和TLR4缺陷的C3H/HeJ小鼠（慢性中耳炎）来表征内耳病理、生理、细胞因子基因表达、细胞因子水平、NF- kB激活的炎症过程和活性氧。本提案的具体目的是：目的1：表征急性中耳炎的内耳炎症特征。这将验证急性中耳炎引起以Thl炎症过程为特征的短暂内耳免疫反应的假设。目的2：表征慢性中耳炎的内耳炎症特征。这将验证慢性中耳炎引起以扩大Th1炎症过程为特征的持续和破坏性内耳免疫反应的假设。内耳病理将通过听觉脑干反应听力学、耳蜗电位、光镜和电子显微镜以及炎症介质的免疫组织化学来测量。耳蜗免疫介导的过程将通过测量炎症因子、细胞因子基因表达、转录因子、血管相关因子和活性氧的ELISA检测来评估。