Identification and optimization of medical countermeasures for phosgene inhalation injuries

Summary
Phosgene gas has been used as a terrorist weapon, in warfare and has injured many Americans in
transportation or industrial accidents. Phosgene targets the lungs, causing severe edema and lung injury after
inhalation, with high lethality in exposure victims. Despite these devastating effects, no mechanism-based
treatment for phosgene injury has been developed.
The renin-angiotensin-aldosterone system (RAAS) plays a key role in cardiopulmonary homeostasis.
However, RAAS is dysregulated during acute respiratory distress syndrome (ARDS) contributing to underlying
pathophysiology. Pro-resolving mediators that are generated during the inflammation cascade are short-lived
due to degradation by an enzyme called soluble epoxide hydrolase (sEH). Several pulmonary studies showed that
inhibition of sEH ameliorated the study outcomes. In our preliminary studies, we noted both dysregulation of
RAAS and pro-resolving epoxides after phosgene inhalation. We found that administration of angiotensin-
converting enzyme (ACE) inhibitors such as Captopril, Enalapril, or Lisinopril improved survival rate, decreased
pulmonary protein leak, and diminished bronchoalveolar inflammatory cell counts. Similarly, when soluble
epoxide hydrolase inhibitors (sEHIs) were administered to mice after phosgene inhalation, the survival rate
significantly improved. Therefore, targeting RAAS and sEH seems to be highly promising. In this application,
based on our strong preliminary data, we hypothesize that targeting the RAAS, including angiotensin-
converting enzyme (ACE) and aldosterone, and stimulating resolution pathways by administration of soluble
epoxide hydrolase inhibitors (sEHIs) post phosgene exposure ameliorates lung injury, leading to decreased
morbidity and improved recovery.
The following aims are proposed: Aim 1: Screen the efficacy of RAAS modulators and sEHIs in mouse
models of phosgene gas-induced lung injury. Aim 2: Determine the pharmacokinetics of the lead drug candidate
and test the efficacy in a 48-hour observation model of swine phosgene gas-induced lung injury. Aim 3:
Determine therapeutic efficacy of the lead candidate in an extended 28-day observation swine model of
phosgene-induced lung injury.
Successful completion of the proposed work will provide pivotal information on the development of
targeted treatment to protect against phosgene gas-induced lung injuries – a critical unmet need, and will
prepare us for Biomedical Research Development Authority (BARDA)-enabling studies and eventual FDA
approval under the animal rule.

Grant Number: 5UG3ES035689-02
NIH Institute/Center: NIH
Principal Investigator: Satyanarayana Achanta