Pathogenesis of Otitis Media with Effusion

中耳炎(OM)是被认为是多因素影响的儿童年龄组的一种常见疾病 在病因学上。而大多数急性发作的有症状的OM病例在一个月内消失 表现，相当大的百分比持续数月至数年，称为渗出性OM(OME)， 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渗出。OME是一种持续性炎症，最常见的是 对传统的药物治疗没有反应。我们最近进行的研究表明， Homps ex Vacuo是一种有效的解释OME在 一些特定的条件。动物咽鼓管功能障碍引起中耳 压力失调反映为压力不足，进而导致渗透率增加 粘膜血管系统的损害并导致ME渗出。但是，负责的机制(S) 用于传递与导致ME的欠压相关的生物信号 粘膜炎症尚不清楚。我们假设相关信号的转导 中耳压力过低会引发和维持炎症过程，从而导致 OME的持久性和对ME生理的不利变化。三个具体目标是 建议检验这一假说：1)确定炎症信号在炎症反应中的作用 ET梗阻后ME积液的产生和持续，2)利用组织培养模型 用于阐明涉及疾病发病机制的特定细胞机制的系统，以及 3)使用生化、药理学和遗传操作来评估key的作用 炎症介质和途径在诱发或维持大鼠胃粘膜病变中的作用 动物OME模型系统。为了实现这些目标，建议使用啮齿类动物进行实验 已建立的OME模型及ME上皮细胞和成纤维细胞组织培养 调查人员。通过这些研究，研究人员希望阐明特定的作用 促进疾病持久性的炎症信号和途径，从而识别 未来治疗干预的潜在目标。

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.