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 postinduction of faecal peritonitis. Control septic animals received vehicle alone. 72-hour survival was significantly greater in statin pre-treated animals (43.7%) compared to both 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 fibers taken from septic animals at 24 hours. 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/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.Short title: Statin and organ dysfunction in sepsis.

Protective Effects of Simvastatin on Endotoxin-Induced Acute Kidney Injury through Activation of Tubular Epithelial Cells’ Survival and Hindering Cytochrome C-Mediated Apoptosis

“…The dose selection of simvastatin was based on the previous rat/murine in vivo studies where the dose range was 10–100 mg/kg/day, considering a rapid upregulation (3- to 10-fold) of HMG-CoA reductase’s activity induced by statin treatment or other inhibitors in rodents. Therefore, the simvastatin doses in this experiment were higher compared to those recommended in clinical medicines [ 14 , 40 , 41 ].…”

Simvastatin Inhibits Endotoxin-Induced Apoptosis in Liver and Spleen Through Up-Regulation of Survivin/NF-κB/p65 Expression

“…We used simvastatin in the previously examined doses (20 or 40 mg/kg per os) that were shown as the protective against the single median lethal dose (LD 50 ) of 22, 15 mg/kg ip of LPS in rats (95% CI 16.5–29.1) (Nežić et al, 2009b). The selected dose of simvastatin were comparable to those that had previously been used in rat/murine studies in vivo (typically 10–100 mg/kg/day), and were higher than those used in humans because of a significant up-regulation (3- to 8-fold) of HMG-CoA reductase induced by statin treatment in rodents (Nežić et al, 2009b; Liu et al, 2012; Morel et al, 2017). In our experimental model of sepsis we challenged the animals with a non-lethal single dose of LPS ip (0.25 LD 50 /kg), a confirmed model that induces the strongest inflammatory effects of the all animal models for acute systemic inflammation, including immune cell infiltration, oxidative stress and apoptosis of organ tissues (Nežić et al, 2009b; Seemann et al, 2017).…”

Simvastatin alleviates bone resorption in apical periodontitis possibly by inhibition of mitophagy‐related osteoblast apoptosis

“…In a rat model of faecal peritonitis, simvastatin treatment prevented the fall in mitochondrial oxygen consumption in muscle fibre taken from septic animals (Morel et al . ). With regard to the influence on osteoblasts, simvastatin was noted to promote the proliferation of human osteoblasts via upregulation of mitochondrial function (Chuang et al .…”

“…Since simvastatin can safeguard mitochondrial function in the state of infection (Morel et al . ), it is interesting to examine whether the protective effect on mitochondria may also take part in its therapeutic mechanism in apical periodontitis.…”