Oxidized Phospholipids in Control of Endothelial Barrier Function: Mechanisms and Implication in Lung Injury

Abstract

Earlier studies investigating the pathogenesis of chronic vascular inflammation associated with atherosclerosis described pro-inflammatory and vascular barrier disruptive effects of lipid oxidation products accumulated in the sites of vascular lesion and atherosclerotic plaque. However, accumulating evidence including studies from our group suggests potent barrier protective and anti-inflammatory properties of certain oxidized phospholipids (OxPLs) in the lung vascular endothelium. Among these OxPLs, oxidized 1-palmitoyl-2-arachdonyl-sn-glycero-3-phosphocholine (OxPAPC) causes sustained enhancement of lung endothelial cell (EC) basal barrier properties and protects against vascular permeability induced by a wide variety of agonists ranging from bacterial pathogens and their cell wall components, endotoxins, thrombin, mechanical insults, and inflammatory cytokines. On the other hand, truncated OxPLs cause acute endothelial barrier disruption and potentiate inflammation. It appears that multiple signaling mechanisms triggering cytoskeletal remodeling are involved in OxPLs-mediated regulation of EC barrier. The promising vascular barrier protective and anti-inflammatory properties exhibited by OxPAPC and its particular components that have been established in the cellular and animal models of sepsis and acute lung injury has prompted consideration of OxPAPC as a prototype therapeutic molecule. In this review, we will summarize signaling and cytoskeletal mechanisms involved in OxPLs-mediated damage, rescue, and restoration of endothelial barrier in various pathophysiological settings and discuss a future potential of OxPAPC in treating lung disorders associated with endothelial barrier dysfunction.

Keywords: OxPAPC; Rho GTPases; endothelial barrier; inflammation; lung injury; oxidized phospholipids; receptor.

Figure 1

Dual role of phospholipids in endothelial function. Full-length oxidized products of phospholipids and some groups of PGs enhance endothelial barrier integrity. In turn, truncated OxPLs and some products of arachidonic acid such as thromboxane and leukotrienes disrupt endothelial barrier.

Figure 2

Mechanisms of OxPLs-mediated regulation of endothelial barrier. OxPAPC-induced activation of S1P1 in Akt or GRP78-dependent manner leads to an increased interaction between various AJ, TJ, and FA proteins resulting in enhancement of endothelial barrier integrity. Similarly, OxPAPC-mediated activation of Rac1 and Rap1 induces cytoskeletal reorganization favoring stabilized junctional assembly. On the other hand, truncated OxPLs-stimulated EC produce ROS that activates Src which phosphorylates tyrosine residues in VE-cadherin causing its internalization, degradation, and ultimately leading to disrupted endothelial barrier. Src also activates VEGFR2 that induces endothelial permeability via enhanced actomyosin contractility caused by increased myosin light chain phosphorylation.