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2-Chlorofatty acids (2-ClFAs) are chlorinated lipid species generated during inflammation, when the antimicrobial enzyme myeloperoxidase (MPO) is released by neutrophils and converts neutrophil-produced hydrogen peroxide into hypochlorous acid (HOCl). HOCl then targets the sn-1 vinyl ether bond of plasmalogens to create 2-chlorofatty aldehydes (2-ClFALDs), which are oxidized by fatty aldehyde dehydrogenase to 2-ClFAs. 2-ClFAs have known effects on human endothelial cells and neutrophils, and increased free 2-ClFA levels in patient plasma are significantly associated with acute respiratory distress syndrome (ARDS) and 30-day mortality in human sepsis patients. 2-ClHA (2-chlorohexadecanoic acid) is the 16C 2-ClFA species. 2-ClHA is known to promote neutrophil adherence to the endothelium and cause the release of von Willebrand factor, angiopoietin-2, and P selectin from human coronary artery endothelial cells. 2-ClHA is also able to induce NETosis in human neutrophils independently of neutrophil activation. However, the molecular mechanisms underlying these effects have yet to be uncovered. The objective of this study was to analyze the proteomic effects of 2-ClHA in human endothelial cells and neutrophils. This was achieved using click chemistry, followed by shotgun proteomics techniques to identify the proteins modified by 2-ClHA in human lung microvascular endothelial cells (HLMVEC) and human neutrophils. It was determined that 2-ClHA covalently modifies proteins associated with endothelial permeability and exocytosis in human lung microvascular endothelial cells, and modifies proteins associated with NETosis in neutrophils. Therefore, the known effects of 2-ClHA on endothelial and neutrophil function may be mediated via the proteins identified using proteomics techniques. Discovery of these processes may lead to improved treatments for sepsis by reducing the negative repercussions of chlorinated lipids while maintaining their beneficial antimicrobial effects. Support provided by NIH grants: R01GM11553, R01ES034383, R01ES035365, and R21ES031562.
Carlson et al. (Fri,) studied this question.