Abstract |
Exposure of biological membranes to reactive oxygen species creates a complex mixture of distinct oxidized phospholipid ( OxPL) species, which contribute to the development of chronic inflammatory diseases and metabolic disorders. While the ability of OxPL to modulate biological processes is increasingly recognized, the nature of the biologically active OxPL species and the molecular mechanisms underlying their signaling remain largely unknown. We have employed a combination of mass spectrometry, synthetic chemistry, and immunobiology approaches to characterize the OxPL generated from the abundant phospholipid 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (PAPC) and investigated their bioactivities and signaling pathways in vitro and in vivo. Our study defines epoxycyclopentenones as potent anti-inflammatory lipid mediators that mimic the signaling of endogenous, pro-resolving prostanoids by activating the transcription factor nuclear factor E2-related factor 2 (Nrf2). Using a library of OxPL variants, we identified a synthetic OxPL derivative, which alleviated endotoxin-induced lung injury and inhibited development of pro-inflammatory T helper (Th) 1 cells. These findings provide a molecular basis for the negative regulation of inflammation by lipid peroxidation products and propose a novel class of highly bioactive compounds for the treatment of inflammatory diseases.
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Authors | Peter Bretscher, Julian Egger, Abdijapar Shamshiev, Martin Trötzmüller, Harald Köfeler, Erick M Carreira, Manfred Kopf, Stefan Freigang |
Journal | EMBO molecular medicine
(EMBO Mol Med)
Vol. 7
Issue 5
Pg. 593-607
(May 2015)
ISSN: 1757-4684 [Electronic] England |
PMID | 25770125
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2015 The Authors. Published under the terms of the CC BY 4.0 license. |
Chemical References |
- 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphorylcholine
- Anti-Inflammatory Agents
- Cyclopentanes
- Eicosanoids
- Epoxy Compounds
- NF-E2-Related Factor 2
- Nfe2l2 protein, mouse
- Phospholipid Ethers
- cyclopentenone
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Topics |
- Animals
- Anti-Inflammatory Agents
(chemistry, metabolism)
- Cyclopentanes
(chemistry, metabolism)
- Eicosanoids
(chemistry, metabolism)
- Epoxy Compounds
(chemistry, metabolism)
- Lung
(pathology)
- Mice, Inbred C57BL
- Mice, Knockout
- NF-E2-Related Factor 2
(metabolism)
- Oxidation-Reduction
- Phospholipid Ethers
(metabolism)
- Th1 Cells
(immunology)
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