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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

EC mitigates sepsis-associated inflammation in vivoA C57BL/6 mice were treated (i.v.) with 500 μg EC or DPPC control 2 h prior to i.p injection of 150 ng/g LPS together with 800 μg/g D-galactosamine. 4 h after LPS application, lungs were perfused with PBS and embedded in paraffin. Tissue sections were hematoxylin-stained to visualize adherent cells. Bars represent 100 ?m.B, C Leukocyte adhesion to lung microvascular endothelium as determined by morphometric image analysis of lung tissue sections is presented for individual vessels in (B) and as averages of single mice in (C). Pooled data of two independent experiments are shown (n = 10 for EC, n = 14 for DPPC). Unpaired two-tailed t-test.D, E C57BL/6 mice were treated with EC or DPPC by intra-tracheal instillation at 18 h (50 μg) and 1.5 h (100 μg) prior to i.p. injection of 150 ng/g LPS and 800 μg/g D-galactosamine. Bar graphs represent absolute numbers of total infiltrating cells and of neutrophils (D). Unpaired two-tailed t-test. Data represent mean ± SEM from one of two independent experiments with at least 6 mice per group. (E) Dot plots depict exemplary gating of lung neutrophils on pregated CD45+ CD11c− SiglecF− BAL cells of EC-/LPS-treated and DPPC-/LPS-treated mice.F, G The concentrations of IL-6 (F) and IL-12 (G) in the BAL of mice treated as in (D) were quantified by ELISA. Data (mean ± SEM) are representative of two independent experiments with 3 mice per group. ****P < 0.0001; unpaired two-tailed t-test.
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fig05: EC mitigates sepsis-associated inflammation in vivoA C57BL/6 mice were treated (i.v.) with 500 μg EC or DPPC control 2 h prior to i.p injection of 150 ng/g LPS together with 800 μg/g D-galactosamine. 4 h after LPS application, lungs were perfused with PBS and embedded in paraffin. Tissue sections were hematoxylin-stained to visualize adherent cells. Bars represent 100 ?m.B, C Leukocyte adhesion to lung microvascular endothelium as determined by morphometric image analysis of lung tissue sections is presented for individual vessels in (B) and as averages of single mice in (C). Pooled data of two independent experiments are shown (n = 10 for EC, n = 14 for DPPC). Unpaired two-tailed t-test.D, E C57BL/6 mice were treated with EC or DPPC by intra-tracheal instillation at 18 h (50 μg) and 1.5 h (100 μg) prior to i.p. injection of 150 ng/g LPS and 800 μg/g D-galactosamine. Bar graphs represent absolute numbers of total infiltrating cells and of neutrophils (D). Unpaired two-tailed t-test. Data represent mean ± SEM from one of two independent experiments with at least 6 mice per group. (E) Dot plots depict exemplary gating of lung neutrophils on pregated CD45+ CD11c− SiglecF− BAL cells of EC-/LPS-treated and DPPC-/LPS-treated mice.F, G The concentrations of IL-6 (F) and IL-12 (G) in the BAL of mice treated as in (D) were quantified by ELISA. Data (mean ± SEM) are representative of two independent experiments with 3 mice per group. ****P < 0.0001; unpaired two-tailed t-test.

Mentions: Our study so far established EC as a potent anti-inflammatory OxPL component that signals through Nrf2 to inhibit pro-inflammatory cytokine and chemokine responses of myeloid cells. We next sought to test the efficacy of EC to inhibit inflammatory responses in a model of sepsis-associated lung inflammation in vivo. For this purpose, mice were intravenously administered with EC or the control phospholipid DPPC 2 h before receiving an intra-peritoneal challenge with a lethal dose of LPS in the presence of D-galactosamine (D-Gal). While systemic LPS/D-Gal application resulted in the massive adhesion of blood mononuclear cells to the microvascular lung endothelium in DPPC-treated control mice, no comparable adhesion was observed after EC pretreatment (Fig5A), which efficiently induced Nrf2 signaling in vivo (Supplementary Fig S4). Instead, the extent of cellular adhesion observed in the lung vasculature of EC-treated animals rather resembled that of naïve controls not treated with LPS (Fig5A). This potent effect of EC was illustrated by a quantitative morphometric analysis confirming that EC pretreatment significantly reduced the number of adherent cells per defined vessel length (Fig5B and C). Prior i.t. administration of EC also efficiently interfered with leukocyte migration into the lung upon i.p. LPS challenge. In particular, EC-treated animals exhibited significantly smaller total infiltrates and reduced absolute neutrophil numbers in their lungs (Fig5D and E) as compared to DPPC-treated controls. Complementing our in vitro findings, EC also strongly decreased the LPS-induced secretion of the pro-inflammatory cytokines IL-6 (Fig5F) and IL-12 (Fig5G) in vivo. Thus, EC efficiently inhibited acute inflammatory responses in vivo and protected mice from sepsis-associated vascular and pulmonary inflammation.


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)

EC mitigates sepsis-associated inflammation in vivoA C57BL/6 mice were treated (i.v.) with 500 μg EC or DPPC control 2 h prior to i.p injection of 150 ng/g LPS together with 800 μg/g D-galactosamine. 4 h after LPS application, lungs were perfused with PBS and embedded in paraffin. Tissue sections were hematoxylin-stained to visualize adherent cells. Bars represent 100 ?m.B, C Leukocyte adhesion to lung microvascular endothelium as determined by morphometric image analysis of lung tissue sections is presented for individual vessels in (B) and as averages of single mice in (C). Pooled data of two independent experiments are shown (n = 10 for EC, n = 14 for DPPC). Unpaired two-tailed t-test.D, E C57BL/6 mice were treated with EC or DPPC by intra-tracheal instillation at 18 h (50 μg) and 1.5 h (100 μg) prior to i.p. injection of 150 ng/g LPS and 800 μg/g D-galactosamine. Bar graphs represent absolute numbers of total infiltrating cells and of neutrophils (D). Unpaired two-tailed t-test. Data represent mean ± SEM from one of two independent experiments with at least 6 mice per group. (E) Dot plots depict exemplary gating of lung neutrophils on pregated CD45+ CD11c− SiglecF− BAL cells of EC-/LPS-treated and DPPC-/LPS-treated mice.F, G The concentrations of IL-6 (F) and IL-12 (G) in the BAL of mice treated as in (D) were quantified by ELISA. Data (mean ± SEM) are representative of two independent experiments with 3 mice per group. ****P < 0.0001; unpaired two-tailed t-test.
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fig05: EC mitigates sepsis-associated inflammation in vivoA C57BL/6 mice were treated (i.v.) with 500 μg EC or DPPC control 2 h prior to i.p injection of 150 ng/g LPS together with 800 μg/g D-galactosamine. 4 h after LPS application, lungs were perfused with PBS and embedded in paraffin. Tissue sections were hematoxylin-stained to visualize adherent cells. Bars represent 100 ?m.B, C Leukocyte adhesion to lung microvascular endothelium as determined by morphometric image analysis of lung tissue sections is presented for individual vessels in (B) and as averages of single mice in (C). Pooled data of two independent experiments are shown (n = 10 for EC, n = 14 for DPPC). Unpaired two-tailed t-test.D, E C57BL/6 mice were treated with EC or DPPC by intra-tracheal instillation at 18 h (50 μg) and 1.5 h (100 μg) prior to i.p. injection of 150 ng/g LPS and 800 μg/g D-galactosamine. Bar graphs represent absolute numbers of total infiltrating cells and of neutrophils (D). Unpaired two-tailed t-test. Data represent mean ± SEM from one of two independent experiments with at least 6 mice per group. (E) Dot plots depict exemplary gating of lung neutrophils on pregated CD45+ CD11c− SiglecF− BAL cells of EC-/LPS-treated and DPPC-/LPS-treated mice.F, G The concentrations of IL-6 (F) and IL-12 (G) in the BAL of mice treated as in (D) were quantified by ELISA. Data (mean ± SEM) are representative of two independent experiments with 3 mice per group. ****P < 0.0001; unpaired two-tailed t-test.
Mentions: Our study so far established EC as a potent anti-inflammatory OxPL component that signals through Nrf2 to inhibit pro-inflammatory cytokine and chemokine responses of myeloid cells. We next sought to test the efficacy of EC to inhibit inflammatory responses in a model of sepsis-associated lung inflammation in vivo. For this purpose, mice were intravenously administered with EC or the control phospholipid DPPC 2 h before receiving an intra-peritoneal challenge with a lethal dose of LPS in the presence of D-galactosamine (D-Gal). While systemic LPS/D-Gal application resulted in the massive adhesion of blood mononuclear cells to the microvascular lung endothelium in DPPC-treated control mice, no comparable adhesion was observed after EC pretreatment (Fig5A), which efficiently induced Nrf2 signaling in vivo (Supplementary Fig S4). Instead, the extent of cellular adhesion observed in the lung vasculature of EC-treated animals rather resembled that of naïve controls not treated with LPS (Fig5A). This potent effect of EC was illustrated by a quantitative morphometric analysis confirming that EC pretreatment significantly reduced the number of adherent cells per defined vessel length (Fig5B and C). Prior i.t. administration of EC also efficiently interfered with leukocyte migration into the lung upon i.p. LPS challenge. In particular, EC-treated animals exhibited significantly smaller total infiltrates and reduced absolute neutrophil numbers in their lungs (Fig5D and E) as compared to DPPC-treated controls. Complementing our in vitro findings, EC also strongly decreased the LPS-induced secretion of the pro-inflammatory cytokines IL-6 (Fig5F) and IL-12 (Fig5G) in vivo. Thus, EC efficiently inhibited acute inflammatory responses in vivo and protected mice from sepsis-associated vascular and pulmonary inflammation.

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