Anti-Inflammatory Effects of OxPAPC Involve Endothelial Cell-Mediated Generation of LXA4.

Abstract

RATIONALE:

Oxidation of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC) generates a group of bioactive oxidized phospholipid products with a broad range of biological activities. Barrier-enhancing and anti-inflammatory effects of OxPAPC on pulmonary endothelial cells are critical for prevention of acute lung injury caused by bacterial pathogens or excessive mechanical ventilation. Anti-inflammatory properties of OxPAPC are associated with its antagonistic effects on Toll-like receptors and suppression of RhoA GTPase signaling.

OBJECTIVE:

Because OxPAPC exhibits long-lasting anti-inflammatory and lung-protective effects even after single administration in vivo, we tested the hypothesis that these effects may be mediated by additional mechanisms, such as OxPAPC-dependent production of anti-inflammatory and proresolving lipid mediator, lipoxin A4 (LXA4).

METHODS AND RESULTS:

Mass spectrometry and ELISA assays detected significant accumulation of LXA4 in the lungs of OxPAPC-treated mice and in conditioned medium of OxPAPC-exposed pulmonary endothelial cells. Administration of LXA4 reproduced anti-inflammatory effect of OxPAPC against tumor necrosis factor-α in vitro and in the animal model of lipopolysaccharide-induced lung injury. The potent barrier-protective and anti-inflammatory effects of OxPAPC against tumor necrosis factor-α and lipopolysaccharide challenge were suppressed in human pulmonary endothelial cells with small interfering RNA-induced knockdown of LXA4 formyl peptide receptor-2 (FPR2/ALX) and in mFPR2-/- (mouse formyl peptide receptor 2) mice lacking the mouse homolog of human FPR2/ALX.

CONCLUSIONS:

This is the first demonstration that inflammation- and injury-associated phospholipid oxidation triggers production of anti-inflammatory and proresolution molecules, such as LXA4. This lipid mediator switch represents a novel mechanism of OxPAPC-assisted recovery of inflamed lung endothelium.

• Authors: Yunbo Ke, Noureddine Zebda, Olga Oskolkova, Taras Afonyushkin, Evgeny Berdyshev, Yufeng Tian, Fanyong Meng, Nicolene Sarich, Valery N Bochkov, Ji Ming Wang, Anna A Birukova, Konstantin G Birukov
• Journal: Circulation research (Circ Res) Vol. 121 Issue 3 Pg. 244-257 (Jul 21 2017) ISSN: 1524-4571 [Electronic] United States
• PMID: 28522438 (Publication Type: Journal Article)
• Copyright: © 2017 American Heart Association, Inc.

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Lipoxins
• Phosphatidylcholines
• lipoxin A4
• oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine

Topics

• Acute Lung Injury (metabolism, prevention & control)
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology, therapeutic use)
• Cells, Cultured
• Endothelial Cells (drug effects, metabolism)
• Humans
• Lipoxins (metabolism, pharmacology, therapeutic use)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Phosphatidylcholines (pharmacology, therapeutic use)
• Treatment Outcome