Significance: Endothelial barrier damage, which is in part caused by excess production of reactive
oxygen,
halogen and
nitrogen species (ROHNS), especially
peroxynitrite (ONOO-), is a major event in early
sepsis and, with leukocyte hyperactivation, part of the generalized dysregulated immune response to
infection, which may even become a complex maladaptive state. Selenoenzymes have major
antioxidant functions. Their synthesis is related to the need to limit deleterious
oxidant redox cycling by small selenocompounds, which may be of therapeutic cytotoxic interest. Plasma
selenoprotein-P is crucial for
selenium transport from the liver to the tissues and for
antioxidant endothelial protection, especially against ONOO-. Above micromolar concentrations,
sodium selenite (Na2SeO3) becomes cytotoxic, with a lower cytotoxicity threshold in activated cells, which has led to
cancer research. Recent Advances: Plasma
selenium (<2% of total body
selenium) is mainly contained in
selenoprotein-P, and concentrations decrease rapidly in the early phase of
sepsis, because of increased
selenoprotein-P binding and downregulation of hepatic synthesis and excretion. At low concentrations, Na2SeO3 acts as a
selenium donor, favoring
selenoprotein-P synthesis in physiology, but probably not in the acute phase of
sepsis. Critical Issues: The cytotoxic effects of Na2SeO3 against hyperactivated leukocytes, especially the most immature forms that liberate ROHNS, may be beneficial, but they may also be harmful for activated endothelial cells. Endothelial protection against ROHNS by
selenoprotein-P may reduce Na2SeO3 toxicity, which is increased in
sepsis. Future Direction: The combination of
selenoprotein-P for endothelial protection and the cytotoxic effects of Na2SeO3 against hyperactivated leukocytes may be a promising intervention for early
sepsis. Antioxid. Redox Signal. 37, 998-1029.