# Pulmonary Pathophysiologic Mechanisms of Chloropicrin and Phosgene

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2024 · $483,000

## Abstract

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.

## Key facts

- **NIH application ID:** 10907752
- **Project number:** 5R01ES034419-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Laura S Van Winkle
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $483,000
- **Award type:** 5
- **Project period:** 2023-08-15 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10907752

## Citation

> US National Institutes of Health, RePORTER application 10907752, Pulmonary Pathophysiologic Mechanisms of Chloropicrin and Phosgene (5R01ES034419-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10907752. Licensed CC0.

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