Pathogenesis of Otitis Media with Effusion

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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.