PATHOGENESIS OF MUCOSAL INFLAMMATION

粘膜炎症的发病机制

• 批准号: 6642896
• 负责人: Patricia A Hebda
• 金额: $ 19.72万
• 依托单位: CHILDREN'S HOSP PITTSBURGH/UPMC HLTH SYS
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6642896
• 关键词: biological signal transduction; cytokine; disease /disorder model; ear infection; eustachian tube; histopathology; immunomodulators; in situ hybridization; inflammation; laboratory rat; model design /development; mucosa; nonhuman therapy evaluation; otitis media; pathologic process; respiratory airway pressure; respiratory gas transport; tissue /cell culture

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.

Politzer所描述的与咽鼓管功能障碍相关的真空外积液机制已被本中心的研究者更完整地开发。该机制包括四个偶然相关的时间顺序事件：1）中耳（ME）气体的吸收未减弱（ET功能障碍）; 2）由此产生的ME负压; 3）粘膜脉管系统的渗透性增加;以及4）液体转导到ME空间。该机制得到了其他生物气袋行为研究的支持，并与ME压力调节的数学模型的预测一致。我们最近进行的研究表明，在适当的条件下，真空前水肿是OME发展和持续存在的有效解释。然而，负责转导与负压相关的生物信号并引发ME粘膜炎症的机制尚不清楚，也未进行研究。虽然渗透压和流体静力学效应被认为是辅因子，但生化测定记录了促炎细胞因子和其他化学物质的激发渗出液中的存在，这些化学物质可能具有转导功能，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学的潜在靶标。由于该信号的转导启动了炎症过程，因此它代表了用于呈现粘膜炎症和OME的治疗的潜在靶点。因此，本项目的主要目标是确定信号转导机制，包括：信号的性质（例如，负压、气体成分改变），用于信号识别的传感组件（例如渗透、化学感受、压力感受），对信号的早期细胞反应（例如细胞因子的合成间隙连接中断），炎症化学物质作为次级信号的作用（例如基于脂质的炎症介质、细胞因子）和粘膜对初级和次级信号的生理反应（例如，间隙接合点形成、改变的跨粘膜电位、液体转导、炎性细胞流入）。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，生物化学（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的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口管的所谓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。