Simvastatin pre-treatment improves survival and mitochondrial function in a 3-day fluid-resuscitated rat model of sepsis

Jerome Morel, Iain Hargreaves, David Brealey, Viruna Neergheen, Janne T Backman, Sandro Lindig, Marcus Bläss, Michael Bauer, Daniel F McAuley, Mervyn Singer

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)747-758
JournalClinical science (London, England : 1979)
Volume131
Issue number8
Early online date06 Apr 2017
DOIs
Publication statusPublished - Apr 2017

Keywords

  • Animals
  • Cholesterol, LDL
  • Combined Modality Therapy
  • Cytokines
  • Drug Evaluation, Preclinical
  • Fluid Therapy
  • Gene Expression Profiling
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Kaplan-Meier Estimate
  • Liver
  • Male
  • Mitochondria
  • Muscle, Skeletal
  • Myocardium
  • Oxygen Consumption
  • Rats, Wistar
  • Sepsis
  • Simvastatin
  • Tissue Culture Techniques
  • Ubiquinone
  • Journal Article
  • Randomized Controlled Trial

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