Pathogenesis of Otitis Media with Effusion

描述（由申请人提供）：中耳炎（OM）是儿科年龄组的常见病，病因被认为是多因素的。虽然大多数急性发作的症状性OM病例在一个月内消退，但有相当大比例的OM伴积液（OME）持续数月至数年，许多患有OME的儿童以中耳（ME）粘膜炎症和积液为证据，但没有近期体征和症状。OME是一种持续性炎症，通常对常规药物治疗无效。我们最近进行的研究表明，在某些条件下，排空水肿是OME发生和持续的有效解释。破坏动物耳咽管（ET）功能会导致中耳（ME）压力失调，表现为压力不足，从而导致粘膜血管通透性增加，导致ME积液。然而，负责转导与导致ME粘膜炎症的压力不足相关的生物信号的机制尚不清楚。我们假设，与中耳压力不足相关的信号转导启动并维持了一个炎症过程，该过程有助于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验证这一假设：1)确定炎症信号在ET阻塞后ME积液产生和持续中的作用；2)利用组织培养模型系统阐明参与疾病发病的特定细胞机制；3)利用生化、药理学和遗传操作评估关键炎症介质和途径在动物OME模型系统中引发或维持粘膜变化的作用。为了实现这些目标，研究人员建议使用啮齿动物的OME模型和研究人员已经建立的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中的作用，从而确定未来治疗干预的潜在目标。

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.