The Role of Plasmalogen Mitochondrial and Endothelial Antioxidant Properties in Sepsis

ABSTRACT Sepsis is triggered by bacterial, viral, or fungal infection, and it is characterized by multi-organ failure following an impaired host response. Sepsis ranks highly in both national in-hospital mortality and cost burden in comparison to all diseases. Sepsis treatment over the years has been limited to antibiotics, fluids, and organ support. New treatments are needed, which could potentially target sepsis cellular pathophysiology including excessive oxidative stress, inflammatory overactivation at the blood-endothelium interface, declines in mitochondrial health, and disordered lipid homeostasis. Plasmalogens are a unique class of phospholipids containing a characteristic vinyl ether bond at the sn-1 position, which links the glycerol backbone to the aliphatic chain. The vinyl ether bond is a target of reactive oxygen species (ROS), and thus plasmalogens are antioxidants. My recent studies have shown plasma plasmalogen levels are reduced in human sepsis, which likely reflects sepsis endothelial oxidative stress derived from redox enzymes and electron leakage from the mitochondrial electron transport chain (ETC). Mitochondrial damage by ROS impacts cellular respiration and lipid metabolism which is detrimental to overall cell health. This suggests a protective role for plasmalogens which reside in cell and organellar membranes, including the mitochondria. Lysoplasmalogen (lysoPls), a plasmalogen class lacking an acyl chain at the sn-2 position, is a useful plasmalogen precursor that displays more rapid cell uptake than plasmalogen and still contains the ROS-scavenging vinyl ether bond. Pilot data show that supplementation of lysoPls to human lung microvascular endothelial cells (HLMVECs) reduces cellular oxidative stress and maintains plasmalogen pools in the presence of pathogenic bacteria, and lysoPls supplementation protects HLMVEC barrier integrity in the presence lipopolysaccharide. Taken together, this suggests lysoPls have an ROS-scavenging role and provide critical endothelial protection during septic oxidative stress. Therefore, we hypothesize plasmalogen loss reflects injurious endothelial oxidative stress during sepsis, and plasmalogen replacement may limit oxidative stress, improving outcomes via mitochondrial and endothelial effects. Studies in Aim 1 will include: 1) examining human sepsis plasma plasmalogen levels as outcome predictors in collaboration with Dr. Nuala Meyer (University of Pennsylvania) and 2) testing plasmalogen replacement therapy in the mouse cecal ligation and puncture model of sepsis for protection against mortality and organ failure in collaboration with Dr. Richard Hotchkiss (Washington University). Physician-scientists Drs. Meyer and Hotchkiss will also serve as co-mentors for this training program. Studies in Aim 2 will test mechanisms that plasmalogen augmentation reduces inflammation and oxidative stress in the endothelium, improving endothelial function. Overall, these studies open new research avenues to distinguish sepsis targets and therapeutics and to ultimately improve sepsis patient outcomes, especially given the rise of antibiotic resistance in recent decades.