HMG-CoA Reductase Inhibitor Simvastatin Profoundly Improves Survival in a Murine Model of Sepsis

Abstract

Background-HMG-CoA reductase inhibitors, such as simvastatin, have been shown to exhibit pronounced immunomodulatory effects independent of lipid lowering but to date have not been used to treat severe inflammatory disease such as sepsis. We thus approached the question of whether treatment with simvastatin might improve cardiovascular function and survival in sepsis. Methods and Results-Mice treated with simvastatin and rendered septic by cecal ligation and perforation (CLP) show a mean survival time close to 4 times the value found in untreated mice. This dramatic improvement is based on a complete preservation of cardiac function and hemodynamic status, which are severely impaired in untreated CLP mice [eg, 20 hours after CLP, cardiac output declined from 1.24Ϯ0.09 to 0.87Ϯ0.11 mL · min Ϫ1 · g Ϫ1 in untreated mice (PϽ0.005; nϭ12), while remaining unaltered (1.21Ϯ0.08 mL · min Ϫ1 · g Ϫ1 at baseline and 1.15Ϯ0.1 mL · min Ϫ1 · g

Lovastatin Enhances Clearance of Apoptotic Cells (Efferocytosis) with Implications for Chronic Obstructive Pulmonary Disease

“…In a Klebsiella pneumoniae mouse model of pneumonia, lovastatin delayed bacterial clearance and enhanced dissemination (2). In contrast, statins have consistently improved survival in animal and human bacterial sepsis (16,22,83), implying that the beneficial effects of statins may outweigh their potential deleterious effects.…”

Statins as antiinflammatory and immunomodulatory agents: A future in rheumatologic therapy?

“…The simvastatin-treated animals also did not experience drops in blood pressure or cardiac output while septic. In addition, monocytes obtained from the simvastatintreated mice had significantly reduced adhesion to ECs under physiologic flow conditions compared with those from untreated mice (an effect reversed by mevalonate) (130). A human ex vivo study showed that oxidative stress, known to increase morbidity and mortality in sepsis, may be decreased by simvastatin in patients with sepsis.…”

Prior Statin Therapy Is Associated With a Decreased Rate of Severe Sepsis

“…A recent study demonstrated that simvastatin pretreatment profoundly improves survival in a murine model of sepsis. 8 Another retrospective study showed that statin therapy reduced both overall and attributable mortality in patients with bacteremia. 9 Many cellular and animal models as well as human data suggested a wide variety of mechanisms for these effects.…”