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.
