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| Item Type: | Article |
|---|---|
| Title: | OMT-28, a synthetic analog of 17,18-epoxyeicosatetraenoic acid, mitigates lipopolysaccharide-induced lung injury in mice |
| Creators Name: | Tsubouchi, Hironobu, Inomata, Rika, Yanagi, Shigehisa, Honda, Moeka, Sakai, Katsuya, Konkel, Anne, Lossie, Janine, Schunck, Wolf-Hagen, Nakazato, Masamitsu and Miyazaki, Taiga |
| Abstract: | Acute respiratory distress syndrome (ARDS) is a severe condition characterized by intense lung inflammation. Excessive oxidative stress and sustained inflammation in humans with ARDS compromise the epithelial barrier's integrity, leading to pulmonary edema, hypoxemia, and rapidly progressive respiratory failure. A cytochrome P450 metabolite of eicosapentaenoic acid (EPA), i.e., 17,18-epoxyeicosatetraenoic acid (17,18-EEQ), exhibits potent anti-inflammatory properties. We investigated the therapeutic potential of OMT-28, a metabolically stable synthetic analog of 17,18-EEQ, in a murine model of lipopolysaccharide (LPS)-induced ARDS. OMT-28 or vehicle was administered at 0.5 and 12 h after an administration of LPS. The results demonstrated that compared to the vehicle, the OMT-28 treatment significantly improved the survival rate in the post-injury period. OMT-28 also alleviated LPS-induced inflammatory cell infiltration, inhibited increased vascular permeability, reduced the levels of IL-1β, IL-6, CCL-2, and TNF-α in bronchoalveolar lavage fluid (BALF), and prevented the rise in NF-κB phosphorylation and the decrease in tight junction protein Zonula occludens-1 (ZO-1) expression. The LPS-induced lung injury led to a reduced expression of the NAD+-dependent deacetylase sirtuin-3 (Sirt3) and mitochondrial dysfunction; the OMT-28 treatment inhibited these changes. In vitro, OMT-28 treatment in LPS-stimulated human bronchial epithelial BEAS-2B cells and human alveolar epithelial A549 cells suppressed the expressions of TNF-α, IL-6, and IL-8, maintained epithelial barrier function, and preserved cell viability. SIRT3 silencing abolished the anti-inflammatory and epithelial cell integrity effects of OMT-28 in BEAS-2B cells and A549 cells. Overall, these findings indicate that OMT-28 may protect against LPS-induced lung injury by maintaining SIRT3 expression and mitochondrial function. |
| Keywords: | ARDS, Omega-3 Epoxyeicosanoid, Inflammation, Sirtuin-3, Animals, Mice |
| Source: | European Journal of Pharmacology |
| ISSN: | 0014-2999 |
| Publisher: | Elsevier |
| Volume: | 1007 |
| Page Range: | 178238 |
| Date: | 15 November 2025 |
| Official Publication: | https://doi.org/10.1016/j.ejphar.2025.178238 |
| PubMed: | View item in PubMed |
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