PATHOGENESIS OF MUCOSAL INFLAMMATION

Politzer描述的咽鼓管(ET)功能障碍与渗出性中耳炎(OME)有关的积液真空机制已由我们中心的研究人员更完整地发展出来。这种机制包括四个偶然相关的时间顺序事件：1)中耳(ME)气体的持续吸收(ET功能障碍)；2)由此产生的ME压力不足；3)粘膜血管通透性增加，以及4)液体进入ME空间。这一机制得到了对其他生物气囊行为的研究的支持，并与ME压力调节的数学模型的预测一致。我们最近的研究表明，在适当的条件下，真空积水是OME发展和持续的有效解释。然而，负责传递与低压相关的生物信号(S)并引发ME粘膜炎症的机制尚不清楚，也未被研究。虽然渗透和静水效应被认为是辅助因素，但生化分析证明，在刺激的渗出液中存在促炎细胞因子和其他可能具有转导功能的化学物质，就像对其他病因的OME所证明的那样。因为这个信号的转导启动了炎症过程，所以它是其他病因的潜在靶点。由于这一信号的转导启动了炎症过程，因此它是设计用于呈现粘膜炎症和OME的治疗的潜在靶点。因此，这个项目的主要目标是确定信号转导的机制，包括：信号的性质(例如，低压、改变的气体成分)，用于信号识别的感觉成分(例如，渗透、化学感受、压力感受)，早期细胞对信号的反应(例如细胞因子的合成，缝隙连接的破坏)，炎症化学物质作为二级信号的作用(例如，基于脂质的炎症介质，细胞因子)以及粘膜对初级和二级信号的生理反应(例如，缝隙连接的形成，改变的粘膜跨膜电位，液体转导，炎症细胞的涌入)。实验将涉及体外(细胞培养)和体内模型系统，并将包括组织病理学、生化(蛋白质、信使核糖核酸、脂类)和生理结果。与过去的研究一样，将使用药理探针来确定特定炎症介质在这一过程中的作用。促进粘膜愈合或导致鼓室造瘘管所谓ME并发症的生化变化尚不清楚，将使用上述技术和方法进行研究。

The hydrops ex vacuo mechanism relating Eustachian (ET) dysfunction to otitis media with effusion (OME) descried by Politzer has been more completely developed by investigators at our Center. This mechanism includes four casually related, temporally sequential events: 1) the unabated absorption of middle ear (ME) gases (ET dysfunction); 2) a resultant ME under-pressure ; 3) an increased permeability of the mucosal vasculature, and 4) a transduction of fluid into the ME space. The mechanism is supported by studies of the behavior of other biological gas pockets and is consistent with the predictions of mathematical mod4ls of ME pressure regulation. Recent studies conducted by us showed that hydrops ex vacuo is a valid explanation for the development and persistence of OME under appropriate conditions. However, the mechanism responsible for transducing the biological signal(s) associated with the under-pressure and initiating ME mucosal inflammation is not known, and has not been studied. While osmotic and hydrostatic effects have been implicated as co-factors, biochemical assays document the presence within the provoked effusion of both pro-inflammatory cytokines and other chemicals that may have a transducing function as was demonstrated for OME of other etiologies. Because transduction of this signal initiates the inflammatory process, it represents a potential target for other etiologies. Because transduction of this signal initiates the inflammatory process, it represents a potential target for therapies designed to present mucosal inflammation and OME. Therefore, the primary goal of this project is to define the mechanism for signal transduction including: the nature of the signal (e.g. under-pressure, altered gas composition), the sensory components for signal identification (e.g. osmotic, chemoreceptive, baroreceptive), the early cellular response to the signal (e.g. synthesis of cytokines gap juncture disruption), the role of inflammatory chemicals as secondary signals (e.g. lipid based inflammatory mediators, cytokines) and the physiological response of the mucosa to the primary and secondary signals (e.g. gap juncture formation, altered transmucosal potentials, fluid transduction, inflammatory cell influx). The experiments will involve in vitro (cell culture) and in vivo model systems, and will include histopathological, biochemical (proteins, mRNA, lipids) and physiological outcomes. As in past studies, pharmacological probes will be used to identify the role of specific inflammatory mediators in this process. The biochemical changes that promote healing of the mucosa or cause the purported ME complications of tympanostomy tubes are not yet known, and will be investigated using the above techniques and methods.