Chlorinated Lipids are Potential Mediators of Microcirculatory Dysfunction During Sepsis

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). Previous studies have shown these chlorinated lipids are produced by activated human neutrophils. Our multi‐PI group is testing the hypothesis that these chlorinated lipids are mediators of endothelial dysfunction during sepsis. Initial investigations showed that plasma 2‐ClFA levels were significantly greater in septic patients in comparison to control healthy humans. Similarly, both plasma and cecum levels of 2‐ClFA were elevated in rats subjected to cecal ligation and puncture protocols compared to rats undergoing sham surgeries. Using intravital microscopy, superfusion of the mesenteric microcirculation with physiological levels of the 2‐ClFA molecular species, 2‐chloropalmitic acid, resulted in significant increases in leukocyte rolling and adhesion compared to both vehicle superfusion as well as superfusion with equimolar concentrations of the non‐chlorinated fatty acid, palmitic acid. The mechanism for leukocyte rolling and adhesion likely is mediated through increased surface expression of adhesion molecules since human endothelial cells treated with either 2‐chloropalmitic acid or 2‐chloropalmitaldehyde had significantly increased surface expression of P‐selectin, E‐selectin, VCAM‐1, and ICAM‐1 in comparisons to endothelial cells treated with either vehicle or non‐chlorinated fatty acid or fatty aldehyde (palmitic acid and palmitaldehyde, respectively). Further studies with human microvessel endothelial cells from both lung and mesentery demonstrated that in comparison to palmitic acid and palmitaldehyde both 2‐chloropalmitic acid and 2‐chloropalmitaldehyde reduced endothelial barrier function. These in vivo and in vitro studies support our hypothesis that chlorinated lipids alter endothelial function in the microcirculation. Furthermore, the robust production of chlorinated lipids at the level of the neutrophil/endothelial interface in the microcirculation during sepsis suggests that these lipids potentially mediate endothelial dysfunction during sepsis leading to multi‐organ failure. Support or Funding Information National Institutes of Health Grant GM115553