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Phospholipid oxidation generates potent anti-inflammatory lipid mediators that mimic structurally related pro-resolving eicosanoids by activating Nrf2.

Bretscher P, Egger J, Shamshiev A, Trötzmüller M, Köfeler H, Carreira EM, Kopf M, Freigang S - EMBO Mol Med (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.

No MeSH data available.


Related in: MedlinePlus

In vitro generated OxPAPC preparations represent complex mixtures of OxPL species with distinct bioactivitiesMass spectrometric quantification of a variety of OxPL species obtained by CuSO4-catalyzed oxidation of PAPC for 2 and 24 h. Mean ± SEM of duplicate determinations are shown.Correlation between the abundance of individual OxPL species detected in mixtures of differentially oxidized OxPL preparations and the capacity of the respective overall OxPL mixtures to suppress the IL-12 secretion of thioglycollate-elicited macrophages. Dots represent data of individual OxPAPC preparations.
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fig02: In vitro generated OxPAPC preparations represent complex mixtures of OxPL species with distinct bioactivitiesMass spectrometric quantification of a variety of OxPL species obtained by CuSO4-catalyzed oxidation of PAPC for 2 and 24 h. Mean ± SEM of duplicate determinations are shown.Correlation between the abundance of individual OxPL species detected in mixtures of differentially oxidized OxPL preparations and the capacity of the respective overall OxPL mixtures to suppress the IL-12 secretion of thioglycollate-elicited macrophages. Dots represent data of individual OxPAPC preparations.

Mentions: Both pro- and anti-inflammatory activities of OxPAPC have been reported (Berliner & Watson, 2005; Bochkov et al, 2010), whereas our results primarily revealed an anti-inflammatory effect of various OxPAPC preparations. We reasoned that the overall bioactivity of a given OxPAPC preparation likely results from the combined properties of its components and is thus determined by the relative concentrations of individual pro- and/or anti-inflammatory OxPL species present within the respective OxPAPC mixture. For example, while OxPAPC generated using copper-catalyzed oxidation for 2 h predominantly contained intermediate oxidation products of PAPC, these OxPL species were almost absent after 24 h of oxidation when the strongest bioactivity was detected (Fig2A). Instead, OxPAPC oxidized with copper sulfate for 24 h contained substantial amounts of more complex oxidation products, such as 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC), 1-palmitoyl-2-glutaryl-sn-glycero-3-phosphocholine (PGPC), 1-palmitoyl-2-(5,6-epoxyisoprostane E2)-sn-glycero-3-phosphocholine (PEIPC), and 1-palmitoyl-2-(5,6-epoxyisoprostane A2)-sn-glycero-3-phosphocholine (PECPC) (Fig2A). To identify the anti-inflammatory OxPL species, we therefore deliberately varied both the oxidation times and oxidative agents in order to generate a panel of different OxPAPC preparations that exhibited titrated degrees of anti-inflammatory bioactivity. We then examined the OxPL composition of the differentially oxidized OxPAPC preparations by mass spectrometry analysis and investigated whether the overall bioactivity of these complex OxPL mixtures correlated with the abundance of any of their OxPL components (Fig2B). Our results suggested previously known OxPL, such as PGPC, POVPC, PEIPC, and 1-palmitoyl-2-(5-keto-6-octene-dioyl)-sn-glycero-3-phosphocholine (KOdiAPC) as likely candidates, but also less well-characterized OxPL species including PECPC, or even OxPL of yet undetermined structure. Thus, the correlative analysis of bulk OxPL mixtures indicated a limited number of candidate lipids as potential anti-inflammatory OxPAPC components (Fig2B).


Phospholipid oxidation generates potent anti-inflammatory lipid mediators that mimic structurally related pro-resolving eicosanoids by activating Nrf2.

Bretscher P, Egger J, Shamshiev A, Trötzmüller M, Köfeler H, Carreira EM, Kopf M, Freigang S - EMBO Mol Med (2015)

In vitro generated OxPAPC preparations represent complex mixtures of OxPL species with distinct bioactivitiesMass spectrometric quantification of a variety of OxPL species obtained by CuSO4-catalyzed oxidation of PAPC for 2 and 24 h. Mean ± SEM of duplicate determinations are shown.Correlation between the abundance of individual OxPL species detected in mixtures of differentially oxidized OxPL preparations and the capacity of the respective overall OxPL mixtures to suppress the IL-12 secretion of thioglycollate-elicited macrophages. Dots represent data of individual OxPAPC preparations.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492819&req=5

fig02: In vitro generated OxPAPC preparations represent complex mixtures of OxPL species with distinct bioactivitiesMass spectrometric quantification of a variety of OxPL species obtained by CuSO4-catalyzed oxidation of PAPC for 2 and 24 h. Mean ± SEM of duplicate determinations are shown.Correlation between the abundance of individual OxPL species detected in mixtures of differentially oxidized OxPL preparations and the capacity of the respective overall OxPL mixtures to suppress the IL-12 secretion of thioglycollate-elicited macrophages. Dots represent data of individual OxPAPC preparations.
Mentions: Both pro- and anti-inflammatory activities of OxPAPC have been reported (Berliner & Watson, 2005; Bochkov et al, 2010), whereas our results primarily revealed an anti-inflammatory effect of various OxPAPC preparations. We reasoned that the overall bioactivity of a given OxPAPC preparation likely results from the combined properties of its components and is thus determined by the relative concentrations of individual pro- and/or anti-inflammatory OxPL species present within the respective OxPAPC mixture. For example, while OxPAPC generated using copper-catalyzed oxidation for 2 h predominantly contained intermediate oxidation products of PAPC, these OxPL species were almost absent after 24 h of oxidation when the strongest bioactivity was detected (Fig2A). Instead, OxPAPC oxidized with copper sulfate for 24 h contained substantial amounts of more complex oxidation products, such as 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC), 1-palmitoyl-2-glutaryl-sn-glycero-3-phosphocholine (PGPC), 1-palmitoyl-2-(5,6-epoxyisoprostane E2)-sn-glycero-3-phosphocholine (PEIPC), and 1-palmitoyl-2-(5,6-epoxyisoprostane A2)-sn-glycero-3-phosphocholine (PECPC) (Fig2A). To identify the anti-inflammatory OxPL species, we therefore deliberately varied both the oxidation times and oxidative agents in order to generate a panel of different OxPAPC preparations that exhibited titrated degrees of anti-inflammatory bioactivity. We then examined the OxPL composition of the differentially oxidized OxPAPC preparations by mass spectrometry analysis and investigated whether the overall bioactivity of these complex OxPL mixtures correlated with the abundance of any of their OxPL components (Fig2B). Our results suggested previously known OxPL, such as PGPC, POVPC, PEIPC, and 1-palmitoyl-2-(5-keto-6-octene-dioyl)-sn-glycero-3-phosphocholine (KOdiAPC) as likely candidates, but also less well-characterized OxPL species including PECPC, or even OxPL of yet undetermined structure. Thus, the correlative analysis of bulk OxPL mixtures indicated a limited number of candidate lipids as potential anti-inflammatory OxPAPC components (Fig2B).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.

No MeSH data available.


Related in: MedlinePlus