Pulmonary Pathophysiologic Mechanisms of Chloropicrin and Phosgene

Chloropicrin (CP) and phosgene (PG) are widely available chemical threat agents, yet the mechanisms of in vivo acute toxicity and long-term pathophysiologic impacts are not well understood. CP, which is in current use as a soil fumigant to sterilize fields before planting high value crops and is widely available. CP is known to cause a biphasic death response characterized by lung edema that occurs either in the first 24 hrs or after 8-10 days. This suggests immune cell mediated and tissue repair responses are key to determining outcomes. However our new data also suggests that there is conducting airway and olfactory epithelial injury in the acute phase of toxicity. The cellular targets and the LC50 for mice is not firmly established. The pathogenesis is likely through tissue damage from binding of CP/PG or their metabolites to sulfhydryl (SH) groups in proteins impacting cell viability and potentially modulated by elements of xenobiotic metabolism in various cellular compartments, as well as instigation of an influx of immune cells into the lung, including both macrophages and neutrophils. Our team is well positioned to address the mechanism of action of these chemical threat agents due to our strong research backgrounds in lung injury and repair (Van Winkle), inhalation exposure science of toxic chemicals (Bein) and relation of tissue inflammation to biological responses (Vogel). The central hypotheses are that PG is more potent than CP in inducing toxicity in mice and that adequate repair is dependent on macrophages with functional CYP19A1, the estrogen synthesis enzyme. The hypotheses will be addressed in three Specific Aims that will 1) Define the dose response and acute injury pattern 2). Define the temporal pattern of lung injury and repair and 3) Test the hypothesis that macrophage estrogen synthesis is important for lung tissue repair following CP or PG exposure. These studies will advance our understanding of how acute injury, local metabolism and target cell type and estrogen synthesizing macrophages contribute tooutcomes following in vivo exposures to CP or PG. This will advance our understanding of tissue specific responses, a research area that is, of necessity, best investigated in animal models and which sets the stage for medical interventions.