PATHOGENESIS OF MUCOSAL INFLAMMATION

Politzer所描述的耳咽部（ET）功能障碍与中耳炎伴渗出性中耳炎（OME）相关的空腔积液机制已被本中心的研究人员进一步完善。该机制包括四个随意相关的、时间顺序的事件：1)中耳（ME）气体吸收不减（ET功能障碍）；2)在压力下产生ME；3)粘膜血管通透性增加，4)液体进入ME间隙。这一机制得到了其他生物气穴行为研究的支持，并与ME压力调节数学模型的预测相一致。我们最近进行的研究表明，在适当的条件下，排空水肿是OME发生和持续的有效解释。然而，负责转导与压力不足和启动ME粘膜炎症相关的生物信号的机制尚不清楚，也未进行研究。虽然渗透和流体静力效应被认为是辅助因素，但生化分析表明，在促炎细胞因子和其他化学物质的诱发积液中存在，这些化学物质可能具有转导功能，正如其他病因的OME所证明的那样。由于该信号的转导启动了炎症过程，因此它代表了其他病因的潜在靶标。由于该信号的转导启动了炎症过程，因此它代表了旨在呈现粘膜炎症和OME的治疗的潜在靶点。因此，本项目的主要目标是定义信号转导的机制，包括：信号的性质（如压力不足，气体成分改变），信号识别的感觉成分（如渗透，化学感受，压力感受），对信号的早期细胞反应（如细胞因子的合成缝隙接合破坏），炎症化学物质作为次要信号的作用（如脂质炎症介质，细胞因子）和粘膜对主要和次要信号的生理反应(如缝隙接合形成，粘膜电位改变，流体转导，炎症细胞内流)。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，mRNA，脂质）和生理结果。在过去的研究中，药理学探针将用于确定特定炎症介质在这一过程中的作用。促进粘膜愈合或引起鼓膜造瘘管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.