MECHANISMS OF ALLERGIC SENSITIZATION BY NITROGEN DIOXIDE EXPOSURE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 哮喘是一种以免疫细胞存在为特征的疾病，免疫细胞能够损害肺部，并导致患者呼吸困难。这些免疫细胞形成的一个分子是有毒气体二氧化氮(NO2)，通常被称为空气污染物。目前还完全不清楚NO2是否会导致哮喘，以及它对肺部的作用。由于位于呼吸管的肺上皮细胞可能会接触到相当数量的NO2，而且被认为在哮喘中起着重要作用，因此项目3的重点是研究NO2对肺上皮细胞造成的损害的后果。我们设计了在完好无损的小鼠身上进行的实验，这些小鼠可以通过吸入暴露在NO2中。我们的目标是测试细胞信号事件是否在吸入NO2的病理反应中起重要作用，以及它们是否可能导致哮喘加重和致敏。我们已经确定，吸入NO2会对肺上皮细胞造成损害，并诱导细胞内分子的释放，这些分子通常被细胞表面受体隔离识别。这些细胞内分子的候选受体由呼吸道上皮细胞表达，并在与配体结合时诱导细胞内信号级联反应。我们正在确定这些受体以及细胞内信号分子在吸入NO2导致哮喘加重的小鼠模型中的作用。为此，我们从合作者那里获得了基因敲除小鼠，目前正在培育足够数量的小鼠用于我们的研究。这些研究将为免疫细胞释放的有毒物质对肺部造成损害的机制提供重要的见解，并可能导致防止这种损害发生的药物的开发。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Asthma is a disease characterized by the presence of immune cells, which are capable of damaging the lungs and contributing to the breathing difficulty of patients. One molecule formed by these immune cells is the toxic gas, nitrogen dioxide (NO2), more commonly known as an air pollutant. It is completely unclear whether NO2 contributes to asthma and how it acts on the lung. Since lung epithelial cells, which line the breathing tube, may come in contact with a considerable amount of NO2, and also are believed to play an important role in asthma, the focus of Project 3 is to examine the consequences of NO2-induced damage to the lung epithelial cells. We have designed experiments in intact mice, which can be exposed to NO2 via inhalation. Our objective is to test whether cell signaling events are important in the pathological response to NO2 inhalation and whether they may contribute to asthma exacerbation and sensitization. We have determined that NO2 inhalation causes damage to the lung epithelium and induces the release of intracellular molecules, which are normally sequestered away from recognition by cell surface receptors. Candidate receptors for these intracellular molecules are expressed by airway epithelium and induce intracellular signaling cascades when engaged by ligands. We are determining the role of these receptors, as well as intracellular signaling molecules, in the exacerbation of asthma in a mouse model by inhalation of NO2. To do so, we have obtained knockout mice from collaborators and are currently breeding sufficient numbers of mice for our studies. These studies will provide an important insights into the mechanisms by which toxic agents released by immune cells can cause damage to the lung, and may result in the development of drugs to prevent that damage from occurring.