Abstract
Sepsis, a systemic inflammatory response to pathogenic factors, is a difficult to treat life-threatening condition associated with cytokine and eicosanoid storms and multi-organ damage. Omega-3 polyunsaturated fatty acids, such as eicosapentaenoic (EPA) and docosahexaenoic acid, are the precursors of potent anti-inflammatory lipid mediators, including 17,18-epoxyeicosatetraenoic acid (17,18-EEQ), the main metabolite of EPA generated by cytochrome P450 epoxygenases. Searching for novel therapeutic or preventative agents in sepsis, we tested a metabolically robust synthetic analog of 17,18-EEQ (EEQ-A) for its ability to reduce mortality, organ damage, and pro-inflammatory cytokine transcript level in a mouse model of lipopolysaccharide (LPS)-induced endotoxemia, which is closely related to sepsis. Overall survival significantly improved following preventative EEQ-A administration along with decreased transcript level of pro-inflammatory cytokines. On the other hand, the therapeutic protocol was effective in improving survival at 48 hours but insignificant at 72 hours. Histopathological analyses showed significant reductions in hemorrhagic and necrotic damage and infiltration in the liver. In vitro studies with THP-1 and U937 cells showed EEQ-A mediated repression of LPS-induced M1 polarization and enhancement of IL-4-induced M2 polarization of macrophages. Moreover, EEQ-A attenuated the LPS-induced decline of mitochondrial function in THP-1 cells, as indicated by increased basal respiration and ATP production as well as reduction of the metabolic shift to glycolysis. Taken together, these data demonstrate that EEQ-A has potent anti-inflammatory and immunomodulatory properties that may support therapeutic strategies for ameliorating the endotoxemia.
Highlights
Omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation is associated with improved outcomes in patients with sepsis including reduction of mortality, duration of mechanical ventilation, and intensive care unit length of stay, as shown in a recent meta-analysis of randomized clinical trials (RCTs) [1]
A pilot study suggested that the risk of death from COVID-19 inversely correlates with the red blood cell level of the long-chain n-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) [4]
We examined the effect of EEQ analog (EEQ-A) on an endotoxemia model established by intraperitoneally injecting LPS
Summary
Omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation is associated with improved outcomes in patients with sepsis including reduction of mortality, duration of mechanical ventilation, and intensive care unit length of stay, as shown in a recent meta-analysis of randomized clinical trials (RCTs) [1]. N-3 PUFA-supplementation is currently discussed as potential adjuvant therapy in COVID-19 patients to promote resolution of inflammation [2] and to mitigate the development of cardiovascular complications [3]. Providing a rationale for their use in bacterial sepsis and corona virus-induced hyperinflammation, n-3 PUFAs are the precursors of lipid mediators with potent anti-inflammatory and cell-protective properties. These bioactive lipid mediators include EPA- and DHA-derived epoxyeicosanoids [3, 6] and a family of specialized pro-resolving mediators [7,8,9]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
