# Inhibition of soluble epoxide hydrolase protects against phosgene-induced lung injuries

> **NIH NIH R21** · DUKE UNIVERSITY · 2021 · $241,500

## Abstract

Summary
 Phosgene gas has been used as a terrorist weapon, in warfare and has injured many Americans in
transportation or industrial accidents. Despite its devastating effects, no mechanism-based treatment has been
developed. Soluble epoxide hydrolase (sEH) enzyme mediates the degradation of beneficial epoxyeicosatrienoic
acids (EETs) and other fatty acid epoxides such as ω-3 docosahexaenoic acid (DHA) and eicosapentaenoic acid
(EPA) that mediate anti-inflammatory pathways and stimulate pro-resolving mechanisms.
 sEH enzyme levels and its downstream products have significantly increased in pulmonary disease
models. Phosgene gas causes lipid peroxidation and membrane disruption that leads to alveolar-capillary
barrier dysfunction. Soluble epoxide hydrolase inhibitors (sEHI) mitigated lipopolysaccharide (LPS),
hyperoxia, and angiotensin II-induced acute lung injury (ALI). Further, sEHI also ameliorated chronic
obstructive pulmonary disease (COPD), asthma, bleomycin-induced pulmonary fibrosis, and smoke-induced
chronic lung injuries. In addition to pulmonary indications, sEHIs have shown beneficial therapeutic benefits
in inflammatory diseases, destructive bone diseases, sepsis, cardiovascular diseases, neurodegenerative
diseases, and pain. Some of the sEHI have been tested in clinical trials with encouraging outcomes and no
potential side effects. While the therapeutic effects of sEHIs hold great promise as a broad-spectrum treatment
candidate, these inhibitors have not yet been tested in pulmonary chemical injuries. In this application, we
hypothesize that inhibiting soluble epoxide hydrolase ameliorates phosgene gas-induced lung injury, leading
to decreased morbidity and improved recovery.
 Here, we propose to test the efficacy of three highly potent and selective sEHIs in mouse models of
phosgene inhalation injury, with the goal to identify a lead therapeutic drug candidate as a future human medical
countermeasure. The following aims are proposed: Aim 1: Assess the therapeutic effects of sEH inhibitors in a
mouse model of phosgene gas-induced acute lung injury; Aim 2: Determine the pharmacokinetic profile of the
most potent sEH inhibitor in naïve and phosgene gas-exposed mice; Aim 3: Assess the therapeutic efficacy of
most potent sEH inhibitor in reducing mortality in a mouse model of phosgene gas-induced lung injury.

## Key facts

- **NIH application ID:** 10207055
- **Project number:** 1R21ES033020-01
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Satyanarayana Achanta
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $241,500
- **Award type:** 1
- **Project period:** 2021-08-09 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10207055

## Citation

> US National Institutes of Health, RePORTER application 10207055, Inhibition of soluble epoxide hydrolase protects against phosgene-induced lung injuries (1R21ES033020-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10207055. Licensed CC0.

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