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

被引：35

作者：

Ke, Yunbo ^{[1
]}

Zebda, Noureddine ^{[1
]}

Oskolkova, Olga ^{[1
]}

Afonyushkin, Taras ^{[1
]}

Berdyshev, Evgeny ^{[2
]}

Tian, Yufeng ^{[1
]}

Meng, Fanyong ^{[1
]}

Sarich, Nicolene ^{[1
]}

Bochkov, Valery N. ^{[4
]}

Wang, Ji Ming ^{[3
]}

Birukova, Anna A. ^{[1
]}

Birukov, Konstantin G. ^{[1
]}

机构：

[1] Univ Chicago, Dept Med, Lung Injury Ctr, Sect Pulm & Crit Med, Chicago, IL 60637 USA

[2] Natl Jewish Hlth, Denver, CO USA

[3] NCI, Frederick, MD 21701 USA

[4] Karl Franzens Univ Graz, Inst Pharmaceut Sci, Graz, Austria

来源：

CIRCULATION RESEARCH | 2017年 / 121卷 / 03期

关键词：

endothelial cells; inflammation; lipoxins; lung injury; phospholipids; pulmonary circulation;

D O I：

10.1161/CIRCRESAHA.116.310308

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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-a 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-a 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.

引用

页码：244 / +

页数：21

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