MECHANISMS OF ALLERGIC SENSITIZATION BY NITROGEN DIOXIDE EXPOSURE

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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.