Mast Cell Activation as a Common Mechanism of Pulmonary Toxicity by Chemical Threat Agents - Project Abstract The Department of Homeland Security considers numerous chemical threat agents a concern for human health, specifically those that are acute pulmonary toxicants. In acute lung injury, inflammation is critical thus we propose that inflammation is a common mechanism of lung injury caused by chemical threat agents due to mast cell activation. We and others have shown mast cell activation to be critical in response to a wide range of xenobiotics including nitrogen mustard, ozone, diesel exhaust, insecticides/herbicides, cigarette smoke, heavy metals and nanoparticles as examples. Mast cells are a logical cell type to study in pulmonary injury from chemical threat agents due to 1) their location at interfaces with the external environment (e.g., lung); 2) their roles as sensors for initiating both innate and adaptive immune responses; and 3) their immediate response to danger signals through degranulation and release of preformed mediators. We have demonstrated that mast cell activation is a major contributor to the pulmonary toxicity and inflammation observed following nitrogen mustard (NM), chloropicrin and formaldehyde exposure. Currently there are few shared mechanisms which have been identified between these chemical threat agents, thus identification of common pathways would be beneficial for future therapeutic targets and biomarkers of exposure. Here, we propose two specific aims to provide confirmatory data on the role of mast cells in pulmonary injury resulting from exposure to chloropicrin (fumigant/pesticide) and formaldehyde (industrial chemical). Our overall hypothesis is that activation of mast cells is a common initiating step in recruitment and propagation of immune responses in the lung across several classes of chemical threat agents. In aim 1, we will Confirm the in vivo contribution of mast cells to pulmonary injury and inflammation resulting from chemical threat agents in Cpa3-Cre mast cell deficient mice. In aim 2 we will Determine role of mast cells in lung injury using a novel human lung-on-a-chip model where we have incorporated mast cells. Collectively, our goal is to establish activation of mast cells as a common mechanism across several chemical classes which are linked with pulmonary toxicity. Confirmation of these findings will allow identification and development of novel therapeutic targets for prevention and/or treatment of the effects of these potential chemical warfare agents through targeting of mast cells.
