Chlorolipids: Mediators and Outcome Predictors of Sepsis

Abstract

Sepsis is a serious cause of morbidity and mortality worldwide. Sepsis is the life‐threatening organ dysfunction caused by the dysregulation of the inflammatory response to an infection. One aspect of this immune response is the systemic activation of neutrophils. Intended to combat microbes through phagocytosis, production of reactive oxygen species, and the release of antimicrobial enzymes through degranulation, neutrophil defense mechanisms can also damage host tissue. Neutrophil myeloperoxidase (MPO) catalyzes the production of hypochlorous acid (HOCl). In addition to microbial targets, HOCl can attack the vinyl ether bond of host membrane plasmalogens, releasing 2‐chlorofatty aldehyde (2‐ClFALD), which is oxidized to 2‐chlorofatty acid (2‐ClFA). Collectively, these plasmalogen oxidation products are members of the chlorolipid family. Human plasma levels of the chlorolipid, 2‐ClFA, predict 30‐day mortality and acute respiratory distress syndrome (ARDS) in sepsis patients. Similarly, septic rats have time‐dependent increases in the plasma, lung, kidney, and intestine levels of 2‐ClFA. For these studies rat sepsis was caused by intraperitoneal injections of 15mL of cecal slurry (isolated from donor rats)/kg body weight. In vitro studies using a click chemistry analog of 2‐ClFA have shown 2‐ClFA localizes to the Weibel‐Palade bodies of human coronary artery endothelial cells and induce the release of their contents. Release of von Willebrand factor, angiopoietin‐2, and P‐ and E‐selectin surface expression were caused by 2‐ClFA exposure to endothelial cells from several vascular beds including human coronary artery endothelial cells and human lung microvascular endothelial cells. The release of these molecules elicits endothelial activation/dysfunction including neutrophil and platelet adherence as well as loss of the endothelial permeability barrier. Additionally, 2‐ClFA induces human neutrophils to release their DNA as neutrophil extracellular traps (NETs) in the process known as NETosis, also implicated in organ failure in sepsis. These in vitro studies with human endothelial cells and human neutrophils suggest 2‐ClFA may mediate the microvascular failure associated with sepsis including endothelial dysfunction and microvascular plugging by NETs. Overall, these studies indicate the importance of chlorolipids in sepsis as prognostic biomarkers of human sepsis outcomes and potential mediators of multi‐organ failure associated with sepsis mortality.Support or Funding InformationFord, PI, Multi‐PI R01 grant (GM115553), Chlorinated lipids in sepsis, NIH Ford, PI, Multi‐PI R01 grant (GM129508), Neutrophil‐dependent mediators of sepsis, NIH Pike, PI, F30 Fellowship grant (F30HL142193), Plasmalogen‐Derived Chlorinated Lipids: Mediators of Acute Lung Injury in Sepsis, NIHThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.