Damage to the intestinal epithelial barrier is a hallmark of inflammatory diseases such as necrotizing enterocolitis. Specialized proresolving mediators (SPMs), such as lipoxin A4, resolvin D1, and resolvin E1, which are derived from essential fatty acids, have been shown to aid in resolving inflammation and promote mucosal healing. This study aimed to explore the effects of specific SPMs on intestinal inflammatory response in an early life in vitro model. We established 3-dimensional and 3-dimensional organoid cultures from fetal and pediatric intestines and investigated the effect of an SPM cocktail (lipoxin A4, resolvin D1, and resolvin E1) on gut epithelial maturation and barrier function. An inflammatory response of the gut barrier was provoked by lipopolysaccharide and flagellin stimulations combined with proinflammatory cytokines, tumor necrosis factor-α, and interferon gamma. Additionally, repetitive mechanical wounding was developed to test the effects of the SPM cocktail on 2-dimensional organoid monolayers. Under physiological conditions, we observed no effect of SPM cocktail treatment on gut epithelial maturation. Upon cytokine challenge, there was no modulation of the inflammatory tone of the gut barrier by the SPM cocktail. However, during the repetitive wounding and recovery assay, SPM cocktail treatment accelerated barrier recovery and maintained barrier integrity for 24 hours after repeated injuries. Our findings suggest that the SPM cocktail does not affect bacterial product- or cytokine-induced epithelial inflammation, although it may accelerate epithelial barrier recovery in mechanically wounded monolayers. These results provide valuable insights into the therapeutic potential of SPMs in neonatal intestinal inflammation. SIGNIFICANCE STATEMENT: Using early life intestinal organoid models, we found that although specialized proresolving mediators did not alter cytokine- or bacterial product-induced inflammation, they significantly enhanced epithelial barrier recovery following repeated mechanical injury.
Copyright © 2026 The Author(s). Published by Elsevier Inc. All rights reserved.

Classically activated innate immune cells undergo a metabolic switch to aerobic glycolysis to support effector function. We report that the small-molecule nitroalkene 10-n-octadec-9-enoic acid (NO2-OA) attenuates the Warburg- like phenotype of aerobic glycolysis in lipopolysaccharide (LPS)-activated macrophages, thus inhibiting pro-inflammatory signaling.
RAW264.7 and bone marrow derived macrophage were treated with LPS with and without NO2-OA or 1400W. Pro-inflammatory cytokines were measured by ELISA and protein expression was determined by immunoblot. Central carbon metabolites with and without 13C stable isotope tracing were measured using liquid chromatography-high resolution mass spectrometry.
Overall, the present observations indicate that nitroalkene-induced changes in central carbon metabolism contribute to the anti-inflammatory actions of this class of multi-target lipid signaling mediators. Comparison of macrophage responses to NO2-OA with the inducible nitric oxide synthase (NOS2 and iNOS) inhibitor 1400W affirms that NO2-OA inhibition of NOS2 expression and activity alone was not sufficient to account for the decreases in pro-inflammatory cytokine expression. NO2-OA treatment reduced intracellular succinate levels, which may be attributed to a concomitant reduction in intracellular itaconate and reliance on glutamine, thereby contributing to hypoxia-inducible factor 1α (HIF1α) destabilization observed in LPS-activated macrophages.
The current data provide additional perspective on the actions of this small-molecule electrophile, which is currently in a Phase 2 clinical trial for the treatment of obesity-related chronic pulmonary inflammation and associated airway dysfunction.
Copyright © 2025 Stevenson, O’Brien, Manuel, Uvalle, Buchan, Mullett, Lockwood, Suber, Freeman and Gelhaus.

[This corrects the article DOI: 10.21037/atm-21-3390.].
Copyright © 2025 AME Publishing Company. All rights reserved.

SARS-CoV-2, the causative virus of the COVID-19 global pandemic, leads to a wide variety of responses among patients. Some of them present a very severe phenotype, while others only experience mild symptoms or are even asymptomatic. This differential prognosis is tightly related to the inflammatory status of the patient. Although WHO declared the end of the emergency, the pandemic caused a great socio-sanitary impact in all countries. Thus, the possible outbreak of new biological diseases in the future makes it necessary to deepen the knowledge of this uncontrolled immune response and look for reliable biomarkers to help us predict its potential health impact. Specialized pro-resolving lipid mediators (SPMs) as lipoxins are endogenous mediators synthesized from arachidonic acid in the resolution stage of any inflammatory process. These lipids have pro-resolving actions in several pathological models, including reducing NF-κB-mediated inflammation, and inducing the antioxidant response through the Nrf-2 pathway. Thus, although a potential relationship has already been suggested between low levels of SPMs and COVID-19 severity, their true role as a predictive biomarker is still unknown.
In this study, we have analyzed by ELISA the serum levels of lipoxin A4 (LXA4) in a representative Spanish cohort. We found reduced levels in deceased patients when compared to mild or severe patients, concomitant with a decrease in the LXA4 biosynthetic pathway and an increase in its degradation pathway. Furthermore, we have studied the correlation between the levels of this SPM and several pathology indicators, finding a significant correlation between increased LXA4 levels and a better prognosis of the patients.
We propose to measure systemic LXA4 as a new promising biomarker to predict the survival in patients affected by SARS-CoV-2 and presumably to other viruses that can affect humanity in the future.
Copyright © 2025 Sánchez-García, Jaén, Lozano-Rodríguez, Avendaño-Ortiz, Pascual‐Iglesias, Hurtado-Navarro, López-Collazo, Boscá and Prieto.

The enzymatic oxidation of arachidonic acid is proposed to yield trihydroxytetraene species (termed lipoxins) that resolve inflammation via ligand activation of the formyl peptide receptor, FPR2. While cell and murine models activate signaling responses to synthetic lipoxins, primarily lipoxin A4 (LXA4), there are expanding concerns about the reported biological formation, detection, and signaling mechanisms ascribed to LXA4 and related di- and tri-hydroxy ω-6 and ω-3 fatty acids. The generation and signaling actions of LXA4 and its primary 15-oxo metabolite were assessed in control, lipopolysaccharide-activated, and arachidonic acid-supplemented RAW264.7 and bone marrow-derived macrophages. Despite the expression of catalytically active enzymes required for LXA4 synthesis, both LXA4 and its 15-oxo-LXA4 metabolite were undetectable in all conditions. Moreover, synthetic LXA4 and the membrane-permeable 15-oxo-LXA4 methyl ester, which rapidly de-esterified to 15-oxo-LXA4, displayed no ligand activity for the putative LXA4 receptor FPR2. Alternatively, 15-oxo-LXA4, an electrophilic α,β-unsaturated ketone, alkylates nucleophilic amino acids and can modulate redox-sensitive transcriptional regulatory protein and enzyme function. 15-oxo-LXA4 activated nuclear factor (erythroid related factor 2)-like 2-regulated expression of anti-inflammatory and repair genes and inhibited NF-κB-regulated pro-inflammatory mediator expression. Synthetic LXA4 showed no impact on these macrophage anti-inflammatory and repair responses. In summary, these data show an absence of macrophage LXA4 formation and receptor-mediated signaling actions of synthetic LXA4. Rather, if present in sufficient concentrations, LXA4 and other mono- and poly-hydroxylated unsaturated fatty acids synthesized by macrophages would be readily oxidized to electrophilic α,β-unsaturated ketone products that modulate the redox-sensitive cysteine proteome via G-protein coupled receptor-independent mechanisms.
Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.