Myeloperoxidase-derived 2-chlorofatty acids contribute to human sepsis mortality via acute respiratory distress syndrome.

Sepsis-associated acute respiratory distress syndrome (ARDS) is characterized by neutrophilic inflammation and poor survival. Since neutrophil myeloperoxidase (MPO) activity leads to increased plasma 2-chlorofatty acid (2-ClFA) levels, we hypothesized that plasma concentrations of 2-ClFAs would associate with ARDS and mortality in subjects with sepsis. In sequential consenting patients with sepsis, free 2-ClFA levels were significantly associated with ARDS, and with 30-day mortality, for each log increase in free 2-chlorostearic acid. Plasma MPO was not associated with either ARDS or 30-day mortality but was correlated with 2-ClFA levels. Addition of plasma 2-ClFA levels to the APACHE III score improved prediction for ARDS. Plasma 2-ClFA levels correlated with plasma levels of angiopoietin-2, E selectin, and soluble thrombomodulin. Endothelial cells treated with 2-ClFA responded with increased adhesion molecule surface expression, increased angiopoietin-2 release, and dose-dependent endothelial permeability. Our results suggest that 2-ClFAs derived from neutrophil MPO-catalyzed oxidation contribute to pulmonary endothelial injury and have prognostic utility in sepsis-associated ARDS.