Abstract
Sepsis is defined as the systemic, dysregulated host immune response to an infection that leads to injury to host organ systems and, often, death. Complex interactions between pathogens and their hosts elicit microcirculatory dysfunction. Neutrophil myeloperoxidase (MPO) is critical for combating pathogens, but MPO-derived hypochlorous acid (HOCl) can react with host molecular species as well. Plasmalogens are targeted by HOCl, leading to the production of 2-chlorofatty acids (2-CLFAs). 2-CLFAs are associated with human sepsis mortality, decrease in vitro endothelial barrier function, and activate human neutrophil extracellular trap formation. Here, we sought to examine 2-CLFAs in an in vivo rat sepsis model. Intraperitoneal cecal slurry sepsis with clinically relevant rescue therapies led to ∼73% mortality and evidence of microcirculatory dysfunction. Plasma concentrations of 2-CLFAs assessed 8 h after sepsis induction were lower in rats that survived sepsis than in nonsurvivors. 2-CLFA levels were elevated in kidney, liver, spleen, lung, colon, and ileum in septic animals. In vivo, exogenous 2-CLFA treatments increased kidney permeability, and in in vitro experiments, 2-CLFA also increased epithelial surface expression of vascular cell adhesion molecule 1 and decreased epithelial barrier function. Collectively, these studies support a role of free 2-CLFAs as biomarkers of sepsis mortality, potentially mediated, in part, by 2-CLFA-elicited endothelial and epithelial barrier dysfunction.