Pathogenesis of Otitis Media with Effusion

渗出性中耳炎的发病机制

• 批准号: 7386554
• 负责人: Patricia A Hebda
• 金额: $ 26.3万
• 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 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7386554
• 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

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，被认为是多因素的 在病因学上。虽然大多数急性发作的症状性OM病例在一个月内消退， 在临床表现中，相当大的比例持续数月至数年，表现为OM伴积液（OME）， 并且许多儿童存在OME，其表现为中耳（ME）粘膜炎症， 无近期体征和症状的积液。OME是一种持续性炎症， 对传统的药物治疗无效。我们最近进行的研究显示， 真空性水肿是OME发展和持续存在的有效解释， 一定条件破坏动物的咽鼓管（ET）功能会导致中耳（ME） 压力失调反映为压力不足，这反过来又导致渗透性增加 并导致ME积液。然而，负责的机制 用于转换与导致ME的负压相关的生物信号 粘膜炎症是未知的。我们假设，与细胞凋亡相关的信号转导 中耳负压引发并维持炎症过程， OME的持续性和ME生理学的不利变化。三个具体目标是 为了验证这一假设，我们提出：1）为了确定炎症信号在炎症中的作用， 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理中涉及的特定细胞机制的系统，以及 3)使用生物化学、药理学和遗传学操作来评估关键基因的作用。 炎症介质和途径在激发或维持诱导的粘膜变化中的作用 动物OME模型系统。为了实现这些目标，实验提出了使用啮齿动物 OME模型和ME上皮细胞和成纤维细胞的组织培养物已经通过 调查人员通过这些研究，研究人员希望阐明特定的 炎症信号和途径在促进疾病的持续性，从而确定 未来治疗干预的潜在目标。