title: Simvastatin pre-treatment improves survival and mitochondrial function in a 3-day fluid-resuscitated rat model of sepsis.
abstract: Statins may offer protective effects in sepsis through anti-inflammatory, mitochondrial protection and other actions. We thus evaluated the effects of simvastatin on survival, organ and mitochondrial function, tissue and plasma ubiquinone levels and liver transcriptomics in a 3-day rat model of sepsis. Comparisons of rat plasma simvastatin and ubiquinone levels were made against levels sampled in blood from patients with acute lung injury (ALI) enrolled into a trial of statin therapy. Animals received simvastatin by gavage either pre- or post-induction of faecal peritonitis. Control septic animals received vehicle alone. Seventy-two-hour survival was significantly greater in statin pre-treated animals (43.7%) compared with their statin post-treated (12.5%) and control septic (25%) counterparts (P<0.05). Sepsis-induced biochemical derangements in liver and kidney improved with statin therapy, particularly when given pre-insult. Both simvastatin pre- and post-treatment prevented the fall in mitochondrial oxygen consumption in muscle fibres taken from septic animals at 24 h. This beneficial effect was paralleled by recovery of genes related to fatty acid metabolism. Simvastatin pre-treatment resulted in a significant decrease in myocardial ubiquinone. Patients with ALI had a marked variation in plasma simvastatin acid levels; however, their ubiquinone/low-density lipoprotein (LDL) cholesterol ratio did not differ regardless of whether they were receiving statin or placebo. In summary, despite protective effects seen with statin treatment given both pre- and post-insult, survival benefit was only seen with pre-treatment, reflecting experiences in patient studies.
authors.affiliation: Departement d'anesthesie et reanimation, CHU Saint Etienne, Saint Etienne, France.|Bloomsbury Institute of Intensive Care Medicine, University College London, London WC1E 6BT, U.K.
authors.forename: Jerome
authors.initials: J
authors.lastname: Morel
authors.affiliation: Neurometabolic Unit, National Hospital, Queen Square, London, WC1N 3BG, U.K.
authors.forename: Iain
authors.initials: I
authors.lastname: Hargreaves
authors.affiliation: Bloomsbury Institute of Intensive Care Medicine, University College London, London WC1E 6BT, U.K.
authors.forename: David
authors.initials: D
authors.lastname: Brealey
authors.affiliation: Neurometabolic Unit, National Hospital, Queen Square, London, WC1N 3BG, U.K.
authors.forename: Viruna
authors.initials: V
authors.lastname: Neergheen
authors.affiliation: Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Janne T
authors.initials: JT
authors.lastname: Backman
authors.affiliation: Department of Anaesthesiology and Intensive Care Therapy and Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany.
authors.forename: Sandro
authors.initials: S
authors.lastname: Lindig
authors.affiliation: Department of Anaesthesiology and Intensive Care Therapy and Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Bläss
authors.affiliation: Department of Anaesthesiology and Intensive Care Therapy and Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Bauer
authors.affiliation: Centre for Infection and Immunity, Queen's University of Belfast and Regional Intensive Care Unit, Royal Victoria Hospital, Belfast, U.K.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: McAuley
authors.affiliation: Bloomsbury Institute of Intensive Care Medicine, University College London, London WC1E 6BT, U.K. m.singer@ucl.ac.uk.
authors.forename: Mervyn
authors.initials: M
authors.lastname: Singer
mesh_terms: D000818:Animals; D008078:Cholesterol, LDL / Q000097:blood; D003131:Combined Modality Therapy; D016207:Cytokines / Q000097:blood; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005440:Fluid Therapy / Q000379:methods*; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D008099:Liver / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D018482:Muscle, Skeletal / Q000201:enzymology; D009206:Myocardium / Q000201:enzymology; D010101:Oxygen Consumption / Q000187:drug effects; D017208:Rats, Wistar; D018805:Sepsis / Q000378:metabolism / Q000517:prevention & control*; D019821:Simvastatin / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D046509:Tissue Culture Techniques; D014451:Ubiquinone / Q000378:metabolism
chemical_list: D008078:Cholesterol, LDL; D016207:Cytokines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D014451:Ubiquinone; D019821:Simvastatin; C030571:ubiquinone 9
keywords: mitochondria; organ dysfunction; plasma simvastatin acid; sepsis; statins; ubiquinone