Abstract
Products of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine oxidation bearing cyclopentenone modifications of arachidonoyl moiety exhibit pronounced protective effects on pulmonary endothelial cell (EC) barrier. On the other hand, prostacyclin and its FDA-approved stable synthetic analog, iloprost, also protect lung vascular EC and attenuate lung inflammation caused by bacterial wall lipopolysaccharide (LPS). In this study, we generated phospholipase resistant synthetic phospholipid with arachidonic acid moiety replaced by iloprost (ILO-PC) and investigated its biological effects. In comparison to free ILO, ILO-PC caused sustained EC barrier enhancement. Both, ILO and ILO-PC effects were mediated by activation of Rap1 and Rac1 GTPases and their cytoskeletal effectors PAK1 and cortactin and enhancement of VE-cadherin adherens junctions. ILO and ILO-PC equally efficiently suppressed acute, Rho GTPase-dependent EC hyper-permeability caused by thrombin. However, ILO-PC exhibited more sustained barrier-protective and anti-inflammatory effects in the model of chronic EC dysfunction caused by LPS. ILO-PC also was more potent inhibitor of NFκB signaling and lung vascular leak in the murine model of LPS-induced acute lung injury (ALI). Optical imaging of lungs of LPS-challenged animals monitored over 3 days showed more efficient ALI recovery in animals treated with ILO-PC. In conclusion, this study describes a novel synthetic phospholipid with barrier-enhancing and anti-inflammatory properties superior to existing prostacyclin analogs, which may be used as a prototype for future development of more efficient treatment for ALI and other vascular leak syndromes.
Published Version
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