Purpose of Study Increased levels of oxidized phospholipids generated by oxidation of shed cell membranes have been recently detected in the local circulation and related to the development of acute lung injury and cardiac ischemia. Previous studies have demonstrated that oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC) enhances basal endothelial cell (EC) barrier properties. This study characterized anti-inflammatory effects and barrier regulation in human pulmonary artery EC induced by OxPAPC-like products containing choline (OxPAPC), serine (OxPAPS), ethanolamine (OxPAPE), and glycerophosphate (OxPAPA) head groups.
Methods Barrier-protective properties and anti-inflammatory effects of oxidized phospholipids were characterized using in vitro models of thrombin- and LPS-induced barrier dysfunction. EC permeability changes were assessed by measurements of transendothelial electrical resistance (TER). EC monolayer integrity and cytoskeletal remodeling were evaluated by immunofluorescent analysis of actin rearrangement. Activation of small GTPases was measured by in vitro pull down assays.
Summary All four groups, OxPAPC, OxPAPA, OxPAPS, and OxPAPE, caused sustained concentration-dependent increases in TER accompanied by unique remodeling of actin cytoskeleton characterized by zip-like actin projections and formation of intercollated peripheral actin structures. Remarkably, oxidized phospholipids significantly enhanced recovery phase in thrombin-challenged EC monolayers, which was assessed by TER measurements and immunofluorescent analysis of paracellular gap formation. In addition, EC pretreatment with oxidized phospholipids had protective effect against thrombin- and LPS-induced permeability monitored by TER measurements. Moreover, oxidized phospholipids attenuated thrombin-induced small GTPase Rho activation and myosin light chain phosphorylation, which was accompanied by increased levels of activated Rac and Cdc42.
Conclusions These results demonstrate for the first time barrier-protective effects elicited by different groups of cell membrane-derived oxidized phospholipids associated with acute lung or cardiac injury and suggest a role for phospholipid polar headgroups in modulation of barrier-protective and anti-inflammatory properties of oxidized phospholipids.
AHA SDG (A.A.B.), HL76259, HL75349 (K.G.B.).
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