Pathogenesis of Otitis Media with Effusion

渗出性中耳炎的发病机制

• 批准号: 7190514
• 负责人: Patricia A Hebda
• 金额: $ 26.65万
• 依托单位: CHILDREN'S HOSP PITTSBURGH/UPMC HLTH SYS
• 依托单位国家: 美国
• 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/7190514
• 关键词: Acute; Animal Model; Animals; Apoptosis; Bacterial Infections; Biochemical; Biological; Biological Assay; Biological Models; Blood Vessels; Cell Communication; Cells; Child; Childhood; Clinical; Collagen; Complex; Condition; Culture Media; Cultured Cells; 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; Inflammatory; Inflammatory Response; Intervention; Intervention Trial; Ion Channel; Laboratories; Lamina Propria; Lead; Lymphoid Tissue; Measures; Mediating; Mediator of activation protein; 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; Purpose; Rate; 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

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）： 中耳炎（OM）是儿科年龄组的常见疾病，其病因被认为是多因素的。虽然大多数急性发病的症状性 OM 病例在就诊后一个月内消退，但很大一部分 OM 伴渗出液 (OME) 持续数月至数年，许多儿童出现 OME，表现为中耳 (ME) 粘膜炎症和渗出液，但无症状。最近的体征和症状。 OME 是一种持续性炎症，通常对传统药物治疗无效。我们最近进行的研究表明，真空水肿是对 OME 在某些条件下的发展和持续存在的有效解释。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，进而导致粘膜脉管系统的通透性增加并导致 ME 积液。然而，负责转导与导致 ME 粘膜炎症的负压相关的生物信号的机制尚不清楚。我们假设与中耳负压相关的信号转导会引发并维持炎症过程，从而导致 OME 的持续存在和 ME 生理学的不利变化。提出了三个具体目标来检验这一假设：1）确定炎症信号传导在 ET 阻塞后 ME 积液的产生和持续中的作用，2）利用组织培养模型系统来阐明疾病发病机制中涉及的特定细胞机制和 3) 利用生化、药理学和遗传操作来评估关键炎症介质和途径在激发或维持动物 OME 模型系统中诱导的粘膜变化中的作用。为了实现这些目标，建议使用研究人员已经建立的 OME 啮齿动物模型以及 ME 上皮细胞和成纤维细胞的组织培养物进行实验。通过这些研究，研究人员希望阐明特定炎症信号和途径在促进疾病持续存在中的作用，从而确定未来治疗干预的潜在目标。