MECHANISMS OF ALLERGIC SENSITIZATION BY NITROGEN DIOXIDE EXPOSURE

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。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，导致患者呼吸困难。这些免疫细胞形成的一种分子是有毒气体二氧化氮（NO2），它通常被称为空气污染物。目前还完全不清楚二氧化氮是否会导致哮喘，以及它是如何作用于肺部的。由于肺上皮细胞排列在呼吸管上，可能会接触到大量的NO2，并且被认为在哮喘中起重要作用，因此Project 3的重点是研究NO2诱导的肺上皮细胞损伤的后果。我们在完整的小鼠身上设计了实验，这些小鼠可以通过吸入暴露于NO2。我们的目的是测试细胞信号事件在吸入二氧化氮的病理反应中是否重要，以及它们是否可能导致哮喘加重和致敏。我们已经确定，吸入二氧化氮会导致肺上皮损伤，并诱导细胞内分子的释放，这些分子通常被隔离在细胞表面受体识别之外。这些细胞内分子的候选受体通过气道上皮表达，并在配体参与时诱导细胞内信号级联反应。我们正在确定这些受体的作用，以及细胞内信号分子，在吸入二氧化氮的小鼠哮喘模型中加重。为此，我们从合作者那里获得了敲除小鼠，目前正在为我们的研究培育足够数量的小鼠。这些研究将为了解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，并可能导致药物的开发，以防止这种损害的发生。

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.