Pathogenesis of Otitis Media with Effusion

渗出性中耳炎的发病机制

基本信息

批准号：
7576744
负责人：
Patricia A Hebda
金额：
$ 27.77万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7576744
关键词：
Acute Animal Model Animals Apoptosis Bacterial Infections Biochemical Biological Biological Assay Biological Models Blood Vessels Cell Communication Cell Culture Techniques Cells Child Childhood Clinical Collagen Complex Culture Media Development Disease Disease model Drug usage Edema Epithelial Cells Etiology Eustachian Tube Fibroblasts Future Gap Junctions Gases Growth Factor Healed Hypoxia Immune response Immune system In Vitro Individual Inflammation Inflammation Mediators Inflammatory Inflammatory Response Intervention Intervention Trial Ion Channel Laboratories Lamina Propria Lead Lymphoid Tissue Measures Mediating Medical Metabolism Methods Mitosis Mitotic Modeling Morphology Mucositis Mucous Membrane Obstruction Otitis Media Otitis Media with Effusion Pathogenesis Pathway interactions Permeability Physiological Physiology Process Production Proteins Rattus Research Personnel Rodent Model Role Signal Pathway Signal Transduction Signaling Molecule Signs and Symptoms Stimulus Testing Therapeutic Intervention Tissues Transgenic Animals Wound Healing age group cell type chemokine cytokine effusion genetic manipulation healing inhibitor/antagonist mRNA Expression middle ear migration pressure programs research study response tissue culture

项目摘要

Otitis media (OM) is a common disease of the pediatric age group considered to be multifactorial in etiology. While most cases of symptomatic OM with acute onset resolve within one month of presentation, a significant percentage persists for months to years as OM with effusion (OME), and many children present with OME evidenced by middle ear (ME) mucosal inflammation and effusion without recent signs and symptoms. OME is a persistent inflammation that most often fails to respond to conventional medical therapies. Recent studies conducted by us show that hydrops ex vacuo is a valid explanation for the development and persistence of OME under certain conditions. Disrupting Eustachian tube (ET) function in animals causes middle ear (ME) pressure dysregulation reflected as underpressures, which in turn causes increased permeability of the mucosal vasculature and results in ME effusion. However, the mechanism(s) responsible for transducing the biological signals associated with the underpressure that result in ME mucosal inflammation are not known. We hypothesize that transduction of the signal associated with middle ear underpressure initiates and sustains an inflammatory process that contributes to persistence of OME and to adverse changes in ME physiology. Three Specific Aims are proposed to test this hypothesis: 1) To determine the role of inflammatory signaling in the production and persistence of ME effusion after ET obstruction, 2) To utilize tissue culture model systems for the elucidation of specific cellular mechanisms involved in disease pathogenesis, and 3) To use biochemical, pharmacologic and genetic manipulation to assess the role of key inflammatory mediators and pathways in provoking or sustaining the mucosal changes induced in the animal OME model systems. To achieve these aims, experiments are proposed using rodent models of OME and tissue cultures of ME epithelial cells and fibroblasts already established by the investigators. With these studies the investigators hope to elucidate the role of specific inflammatory signals and pathways in promoting disease persistence, and thus to identify potential targets for future therapeutic interventions.

中耳炎 (OM) 是儿科年龄组的常见疾病，被认为是多因素影响的在病因学上。虽然大多数急性发作的症状性 OM 病例会在 1 个月内消退报告显示，很大一部分 OM 伴积液 (OME) 持续数月至数年，许多儿童患有 OME，表现为中耳 (ME) 粘膜炎症和无近期体征和症状的积液。 OME 是一种持续性炎症，最常见的是对传统的医学疗法没有反应。我们最近进行的研究表明真空中的水是对 OME 的发展和持续存在的有效解释某些条件。破坏动物的咽鼓管 (ET) 功能会导致中耳 (ME) 压力失调表现为压力不足，进而导致渗透性增加粘膜血管系统并导致 ME 积液。然而，负责的机制用于转换与导致 ME 的低压相关的生物信号粘膜炎症尚不清楚。我们假设相关信号的转导中耳低压会引发并维持炎症过程，从而导致 OME 的持续存在以及 ME 生理学的不利变化。三个具体目标是建议检验这一假设：1）确定炎症信号传导在 ET阻塞后ME积液的产生和持续，2）利用组织培养模型用于阐明疾病发病机制中特定细胞机制的系统，以及 3）利用生化、药理学和基因操作来评估关键的作用炎症介质和引起或维持粘膜变化的途径动物 OME 模型系统。为了实现这些目标，建议使用啮齿动物进行实验已经建立的 OME 模型以及 ME 上皮细胞和成纤维细胞的组织培养物调查人员。通过这些研究，研究人员希望阐明特定的作用促进疾病持续存在的炎症信号和途径，从而确定未来治疗干预的潜在目标。