Anti-Inflammatory Effects of OxPAPC Involve Endothelial Cell Mediated Generation of LXA4
Rationale: Oxidation of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine generates a group of bioactive oxidized phospholipid products (OxPAPC) with a broad range of biological activities. Barrier-enhancing and anti-inflammatory effects of OxPAPC on pulmonary endothelial cells (EC) 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 pro-resolving 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 EC. Administration of LXA4 reproduced anti-inflammatory effect of OxPAPC against TNFα in vitro and in the animal model of LPS-induced lung injury. The potent barrier protective and anti-inflammatory effects of OxPAPC against TNFα and LPS challenge were suppressed in human pulmonary EC with siRNA-induced knockdown of LXA4 formyl-peptide receptor-2 (FPR2/ALX) and in mFPR2-/- 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 pro-resolution molecules such as LXA4. This lipid mediator switch represents a novel mechanism of OxPAPC-assisted recovery of inflamed lung endothelium.
- Oxidized phospholipids
- lipoxin A4
- vascular biology
- endothelial cell
- pulmonary circulation
- Received November 10, 2016.
- Revision received May 12, 2017.
- Accepted May 18, 2017.