ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Inflammation Pharmacology
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1652349
Inhibition of soluble epoxide hydrolase in endotoxin induced pig lung injury
Provisionally accepted
Niklas Larsson1*
Cindy B Mcreynolds2
Sung Hee Hwang2
Debin Wan2
Jun Yang2Richard Lindberg3Stefan Lehtipalo1
Jonas Claesson1
Amanda Irgum Liljeström1Alicia Lind1Anders Brolin1Martin Isaksson Mettävainio4
Bruce D. Hammock2
Christophe Morisseau2
Malin Linder Nording2,3- 1Umea Universitet Institutionen for diagnostik och intervention, Umeå, Sweden
- 2University of California Davis Department of Entomology & Nematology, Davis, United States
- 3Umea universitet Kemiska institutionen, Umeå, Sweden
- 4Umea universitet Institutionen for medicinsk biovetenskap, Umeå, Sweden
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
Pharmacological inhibition of soluble epoxide hydrolase has been shown to attenuate lung injury development in rodents exposed to bacterial lipopolysaccharide. To investigate if these effects can be reproduced in larger animals, we tested soluble epoxide hydrolase (sEH) inhibition using an sEH inhibitor 1-adamantanyl-3-{5-[2-(ethylethoxy)ethoxy]pentyl}urea (AEPU) in a porcine model of lipopolysaccharide-induced acute lung injury. AEPU was selected from 23 sEH inhibitors based on IC50 values and metabolic stability profiles established by a fluorescent based activity assay and porcine liver microsomal test, respectively. Hydrolysis of fatty acid epoxides to their corresponding diols is catalyzed by sEH. Inhibition of sEH reduces this conversion, leading to an accumulation of epoxides relative to diols. Hence, AEPU-treated subjects (n=9) showed metabolic signs of effective in vivo inhibition of the target enzyme reflected in an increased epoxide/diol ratio of 12(13)- epoxyoctadecenoic acid to 12,13-dihydroxyoctadecenoic acid compared to placebo-treated controls (p=0.026). However, there was no difference in lung injury development or survival in subjects treated with the rapidly metabolized AEPU compared to placebo-treated controls (n=10). In conclusion, administration of the soluble epoxide hydrolase inhibitor AEPU did not attenuate endotoxin induced lung injury with lipopolysaccharide in pigs under the severe conditions tested here.
Keywords: Acute Respiratory Distress Syndrome, Lung Injury, soluble epoxide hydrolase, AEPU, lipid mediators
Received: 23 Jun 2025; Accepted: 26 Aug 2025.
Copyright: © 2025 Larsson, Mcreynolds, Hwang, Wan, Yang, Lindberg, Lehtipalo, Claesson, Liljeström, Lind, Brolin, Mettävainio, Hammock, Morisseau and Nording. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Niklas Larsson, Umea Universitet Institutionen for diagnostik och intervention, Umeå, Sweden
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.