title: Superoxide anion overproduction in sepsis: effects of vitamin e and simvastatin.
abstract: Oxidative stress during sepsis induces tissue damage, leading to organ dysfunction and high mortality. The antioxidant effects of vitamin E have been reported in several diseases, but not in sepsis. Statins have cholesterol-independent anti-inflammatory effects that are related to a decrease of isoprenoid proteins and oxidative stress. Therefore, we evaluated superoxide anion (O2- degree) production and ex vivo effects of vitamin E and simvastatin in sepsis. Fourteen healthy volunteers, 14 intensive care unit (ICU) nonseptic, and 14 ICU patients with sepsis were included in this prospective study. Plasma cholesterol, triglyceride, and vitamin E levels were determined by routine laboratory tests. Superoxide anion production was measured in the venous blood by chemiluminescence technique after phorbol myristate acetate stimulation. Effects of vitamin E and simvastatin on O2- degree production was investigated ex vivo. Luminescence was indexed to the leukocyte count. We also investigated the in vitro effect of simvastatin on translocation of NADPH oxidase p21 Rac2 subunit in THP-1 monocytic cell line. The ratio of vitamin E/cholesterol + triglycerides was significantly decreased in septic as compared with nonseptic patients and volunteers. The O2- degree production was significantly higher in the group of septic patients than in the others, regardless of the polymorphonuclear leukocyte count. Vitamin E and simvastatin induced ex vivo an inhibition of O2- degree production of 20% and 40% respectively. In vitro, simvastatin inhibited phorbol myristate acetate-induced- O2- degree production by monocytes through NADPH oxidase inactivation. We conclude that sepsis is associated with a significant decrease in vitamin E and an overproduction of O2- degree. Vitamin E and simvastatin lessen this phenomenon through NADPH oxidase inactivation.
authors.affiliation: Intensive Care Unit, Lapeyronie University Hospital, Montpellier, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Durant
authors.forename: Kada
authors.initials: K
authors.lastname: Klouche
authors.forename: Sandrine
authors.initials: S
authors.lastname: Delbosc
authors.forename: Marion
authors.initials: M
authors.lastname: Morena
authors.forename: Laurent
authors.initials: L
authors.lastname: Amigues
authors.forename: Jean Jacques
authors.initials: JJ
authors.lastname: Beraud
authors.forename: Bernard
authors.initials: B
authors.lastname: Canaud
authors.forename: Jean Paul
authors.initials: JP
authors.lastname: Cristol
mesh_terms: D018806:APACHE; D002097:C-Reactive Protein / Q000032:analysis; D002460:Cell Line; D002784:Cholesterol / Q000097:blood; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D018384:Oxidative Stress / Q000187:drug effects*; D012016:Reference Values; D018805:Sepsis / Q000097:blood*; D019821:Simvastatin / Q000627:therapeutic use*; D013481:Superoxides / Q000097:blood*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014280:Triglycerides / Q000097:blood; D014810:Vitamin E / Q000097:blood / Q000627:therapeutic use*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D014280:Triglycerides; D013481:Superoxides; D014810:Vitamin E; D002097:C-Reactive Protein; D002784:Cholesterol; D019821:Simvastatin; D013755:Tetradecanoylphorbol Acetate