Investigating the biochemical mechanisms responsible for multi-organ failure in sepsis.

Death caused by sepsis is increasing in the U.S. and globally. We are examining changes at the blood/blood vessel interface that is altered during sepsis, leading to multi-organ failure.

The Ford lab has discovered molecules derived from activated leukocytes, including chlorinated lipids and reactive aldehyde-containing compounds. These novel molecules are being investigated as mediators of dysfunction at the blood/blood vessel interface. In particular, these molecules have important roles in activating endothelial cells and altering leukocyte function.

In addition to the mechanistic roles of the lipids, we are also determining their potential as prognostic indicators of human sepsis outcomes. For these research programs, we employe a multidisciplinary, collaborative approach, including bio-organic (chemical synthesis and mass spectrometry) techniques, biochemical methods, physiological models, and translational/clinical validation.

Current and future studies are being directed to discovering molecules related to the leukocyte-produced lipids originally revealed by our lab as well as their potential pathophysiological roles. While these studies are based on the activation mechanisms of neutrophils, we are also mining deeper into the human metabolome and lipidome involved in sepsis using untargeted lipidomics and metabolomics approaches.

Research Highlights:

Septic patients with acute respiratory distress syndrome display higher plasma concentrations of free 2-chlorofatty acids.

Compared with subjects who never developed ARDS, those who developed ARDS within the first 6 days of sepsis have higher circulating levels of free 2-ClPA and free 2-ClSA on the day of ICU admission.

From: Myeloperoxidase-derived 2-chlorofatty acids contribute to human sepsis mortality via acute respiratory distress syndrome. Meyer NJ, Reilly JP, Feng R, Christie JD, Hazen SL, Albert CJ, Franke JD, Hartman CL, McHowat J, Ford DA. J Clin Invest Insight 2(23):e96432, 2017 (PMID: 29212955).

2-Chlorofatty acids localize to the endothelial cell Weibel Palade bodies leading to their mobilization.

Human coronary artery endothelial cells were treated with the click-chemistry analog of 2-chloropalmitic acid. The click analog was clicked to an azide-TAMRA (red) to visualize the localization of 2-chloropalmitic acid. This co-localized with P-selectin and von Willebrand Factor (VWF) indicating the selective localization of 2-chloropalmitic acid with the Weibel Palade bodies..

From: 2-Chlorofatty acids induce Weibel-Palade body mobilization. Hartman CL, Duerr MA, Albert CJ, Neumann WL, McHowat J, Ford DA. J Lipid Res 59(1):113-122, 2018 (PMID: 29167411).

2-Chlorofatty acids make neutrophils go NETs.

Neutrophil extracellular traps (green strands/nets in image under 2-ClPA, 2-chloropalmitic acid) are selectively produced compared to palmitic acid. PMA (phorbol myristate acetate) is shown as a positive control for NET formation.

From: 2-Chlorofatty acids: Lipid mediators of neutrophil extracellular trap formation. Palladino END, Katunga LA, Kolar GR, Ford DA. J Lipid Res 59(8):1424-1432, 2018 (PMID: 29739865).