%0 Journal Article %A Yunbo Ke %A Yue Li %A Kamoltip Promnares %A Anna Birukova %A Konstantin Birukov %T Esterification of iloprost enhances its protective effects on pulmonary endothelium %D 2020 %R 10.1183/23120541.RFMVC-2020.21 %J ERJ Open Research %P 21 %V 6 %N suppl 4 %X Correction of endothelial (EC) barrier dysfunction and inflammation in ALI/ARDS represents an important problem. Previous studies demonstrate beneficial effects of prostacyclin and its stable analog iloprost. In this study, we generated phospholipase resistant synthetic phospholipid with arachidonic acid moiety replaced by iloprost (iloprost-NH-PC) and performed comparative analysis of free iloprost and iloprost-NH-PC effects. Iloprost-NH-PC caused more sustained barrier enhancement monitored by measurements of electrical resistance and permeability assays. Both, iloprost and iloprost-NH-PC effects were associated with activation of Rap1 and Rac1 GTPases, their cytoskeletal effectors PAK1 and cortactin and enhancement of VE-cadherin adherens junctions. Both compounds equally efficiently suppressed acute EC hyper-permeability caused by thrombin. However, iloprost-NH-PC exhibited sustained anti-inflammatory effects in models of chronic EC dysfunction by causing more pronounced inhibition of NFkB signaling, expression of adhesion molecules ICAM1, VCAM1, and cytokine release. Iloprost-NH-PC also was more potent in vivo in inhibiting LPS-induced lung vascular leak monitored by Evans blue extravasation, suppression of LPS-induced increases in cell count, protein content in lavage fluid, and cytokine production. Optical imaging of lungs of LPS-challenged animals showed more efficient ALI recovery in animals treated with iloprost-NH-PC. This study describes a novel synthetic phospholipid with barrier-enhancing and anti-inflammatory properties superior to existing prostacyclin analogs, which may be used as prototype for future development of efficient treatment for ALI and other vascular leak syndromes.FootnotesCite this article as: ERJ Open Research 2020; 6: Suppl. 4, 21.This is an ERS Respiratory Failure and Mechanical Ventilation Conference abstract. No full-text version is available. Further material to accompany this abstract may be available at www.ers-education.org (ERS member access only). %U