Abstract 1823 Plasmalogen derived products of reactive chlorinating species targeting: A family of bioactive electrophilic lipids

Plasmalogen phospholipids contain a vinyl ether bond that is targeted by hypochlorous acid (HOCl) produced by myeloperoxidase activity in activated leukocytes. The product of plasmalogen oxidation by HOCl is 2-chlorofatty aldehyde (2-ClFALD), which in turn can be oxidized to 2-chlorofatty acid (2-ClFA). Plasmalogens have 16- and 18-carbon aliphatic groups that generate these chlorinated lipids. We have recently shown human neutrophils have very long chain plasmalogens, which are also targeted by HOCl to generate very long chain 2-ClFALD and 2-ClFA. Plasma plasmalogens decrease during human sepsis. Increases in plasma levels of 2-ClFA are associated with acute respiratory distress syndrome caused 30-day mortality in intensive care unit patients with sepsis. Additionally in septic patients increased plasma 2-ClFA levels associate with plasma biomarkers of endothelial and platelet activation. In cell studies, 2-ClFA elicits endothelial activation characterized by P-selectin surface expression, von Willebrand factor release, and angiopoietin-2 release as well as the phenotypic changes associated with these factors including neutrophil adhesion, platelet adhesion, and permeability barrier dysfunction, respectively. 2-ClFA also elicits neutrophil extracellular trap formation. Click chemistry analogs of 2-ClFA have been used to demonstrate 2-ClFA localizes to the endothelial Weibel Palade bodies, which are the storage granules for P-selectin, von Willebrand factor, and angiopoietin-2. The click analog has also been employed to identify proteins modified by 2-ClFA in endothelial cells and neutrophils. The electrophilic chlorinated carbon of 2-ClFALD and 2-ClFA are reactive with cysteine residues resulting in protein alkylation. In summary, plasmalogens are targets of reactive oxygen species and targeting by HOCl leads to the production of the chlorinated lipidome. These chlorinated lipids have profound effects on neutrophils and endothelium likely through their electrophilic properties. This project was supported by National Institutes of Health R01 GM-115553, R01 ES-034383, R21 ES-031562 and S10OD025246 to DAF.