Abstract
Neutrophilic inflammation is a component of sepsis‐associated acute respiratory distress syndrome (ARDS). Neutrophil myeloperoxidase (MPO) activity produces HOCl, which leads to increased plasma 2‐chlorofatty acid (2‐ClFA) levels due to HOCl targeting plasmalogens. Thus, these studies were designed to investigate the role of 2‐ClFA in ARDS during sepsis. In patients with sepsis (n=198), free 2‐ClFA levels were significantly associated with ARDS (odds ratio (OR) 1.87 (95% CI 1.41, 2.49); p < 0.001), and with 30‐day mortality (OR 1.38 (95% CI 1.11, 1.72); p=0.004), for each log increase in free 2‐chlorostearic acid. Of considerable interest, plasma 2‐ClFA levels correlated with plasma levels of angiopoietin‐2, E‐selectin, and soluble thrombomodulin suggesting 2‐ClFAs may mediate endothelial dysfunction in human sepsis. Further studies with human lung microvascular endothelial cells (HMVEC‐L) showed 2‐ClFA treatment resulted in increased adhesion molecule surface expression; increased angiopoietin‐2 release and dose‐dependent endothelial permeability. In contrast, these changes were not observed in endothelial cells treated with non‐chlorinated palmitic acid. Next, the cecal slurry model of rat sepsis was investigated. Injecting rats with 15ml of cecal slurry/kg resulted in mortality within 26h accompanied by significant increases in 2‐ClFA levels in the plasma and lung in comparison to rats injected with vehicle. The ultimate goal of these studies will be to test therapeutic agents that prevent chlorinated lipid‐caused organ injury including ARDS during sepsis. Collectively, these studies suggest that 2‐ClFAs derived from neutrophil MPO‐catalyzed oxidation contribute to pulmonary endothelial injury and ARDS, and have prognostic utility in sepsis‐associated ARDS.Support or Funding InformationThis study was supported by NIH grants R01GM115553 (to DAF and JM). and R01HL122474 (to NJM).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Published Version
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