Many occupational and environmental air polutants initiate immediate nasal responses via interaction with nasal trigeminal C fibers. Such responses are very important from an inhalation toxicological perspective as evidenced by the fact that one-half of current occupational exposure guidelines are based on this response. The characteristic decrease in breathing frequency that results from such sensory irritants is well studied, however, the local nasal mucosal effects are very poorly defined despite the fact that stimulation of nasal trigeminal C fibrers is known to result in the release of a variety of potent mediators including substance P. Substance P exerts a variety of effects in human and rodent nasal mucosa including vasodilation and increased blood flow, increased vascular permeability leading to edemagenesis, and mucous hypersecretion. The goal of the proposed research is to gain an integrated understanding of the acute response of the nasal mucosa to inspired irritants. The central hypothesis of this proposal is that the sensory irritant response includes a specific and consistent array of effects in the nasal mucosa that are mediated in part by substance P and differ somewhat in the rat and mouse. The proposed research will characterize the immediate nasal responses in the mouse and rat to four toxic irritants: acrolein, ethyl acrylate, acetaldehyde and nitrogen dioxide. In addition, the role of substance P in the immediate response to these toxicants will be studied via the use of a substance P antagoist and via inhibition of substance P degradation pathways through use of peptidase inhibitors. Animal inhalation toxicity studies are an essential tool for assessing potential adverse health effects of occupational and environmental air pollutants. Our ability to fully understand the acute irritant response in humans has been hampered by the lack of data that can be directly and quantitatively compared between animals and humans. The proposed research is aimed at filling this gap by increasing our understanding of the integrated response to such agents. In the long-term, this will serve to significantly enhance our ability to predict and evaluate the potential adverse health effects of irritant air pollutants.
