Simvastatin Decreases Lipopolysaccharide-induced Pulmonary Inflammation in Healthy Volunteers

Abstract

Rationale: Simvastatin inhibits inflammatory responses in vitro and in murine models of lung inflammation in vivo. As simvastatin modulates a number of the underlying processes described in acute lung injury (ALI), it may be a potential therapeutic option. Objectives: To investigate in vivo if simvastatin modulates mechanisms important in the development of ALI in a model of acute lung inflammation induced by inhalation of lipopolysaccharide (LPS) in healthy human volunteers. Methods: Thirty healthy subjects were enrolled in a double-blind, placebo-controlled study. Subjects were randomized to receive 40 mg or 80 mg of simvastatin or placebo (n 5 10/group) for 4 days before inhalation of 50 mg LPS. Measurements were performed in bronchoalveolar lavage fluid (BALF) obtained at 6 hours and plasma obtained at 24 hours after LPS challenge. Nuclear translocation of nuclear factor-kB (NF-kB) was measured in monocyte-derived macrophages. Measurements and Main Results: Pretreatment with simvastatin reduced LPS-induced BALF neutrophilia, myeloperoxidase, tumor necrosis factor-a, matrix metalloproteinases 7, 8, and 9, and C-reactive protein (CRP) as well as plasma CRP (all P , 0.05 vs. placebo). There was no significant difference between simvastatin 40 mg and 80 mg. BALF from subjects post-LPS inhalation induced a threefold up-regulation in nuclear NF-kB in monocyte-derived macrophages (P , 0.001); pretreatment with simvastatin reduced this by 35% (P , 0.001). Conclusions: Simvastatin has antiinflammatory effects in the pulmonary and systemic compartment in humans exposed to inhaled LPS. Clinical trial registered with www.controlled-trials.com (ISRCTN21056528).

Simvastatin in the Acute Respiratory Distress Syndrome

“…We used simvastatin at a dose of 80 mg on the basis of our previous data from clinical studies, 4,5 in which simvastatin improved surrogate outcomes and biologic mechanisms implicated in ARDS. The data from our current study and the SAILS trial show that neither a lipophilic statin (simvastatin) nor a hydrophilic statin (rosuvastatin) is effective in the treatment of ARDS.…”

“…3 Simvastatin reduced pulmonary and systemic inflammatory responses in a human model of ARDS induced by lipopolysaccharide inhalation. 4 In addition, in a small, single-center, randomized, placebo-controlled study involving patients with acute lung injury, simvastatin ameliorated nonpulmonary organ dysfunction and was safe. 5 That phase 2 study was not designed or powered to show an effect of simvastatin on clinical outcomes.…”

Update on Acute Lung Injury and Critical Care Medicine 2009

“…Pretreatment with simvastatin reduced endotoxin-induced alveolar neutrophilia, myeloperoxidase, TNF-a, and matrix metalloproteinases 7, 8, and 9. Thus, this clinical study paves the way for further therapeutic evaluation of statins in patients with ALI (70).…”

Statins in patients with sepsis and ARDS: is it over? We are not sure

“…A metaanalysis of 13 studies involving 254,950 patients found that treatment with statins in community-acquired pneumonia was associated with improved survival but that the effect was more pronounced if treatment was initiated in the community prior to hospital admission [15]. This is supported by data that pretreatment with simvastatin attenuated the systemic and pulmonary inflammatory response to lipopolysaccharide (LPS) in healthy human subjects [10]. Future studies could focus on randomising patients at high risk of ARDS, such as patients undergoing high-risk surgery such as oesophagectomy, to pretreatment with statins.…”

“…As for sepsis, data from recent large, multicentre, double-blind, randomised, placebo-controlled clinical trials in patients with ARDS have shown that, despite promising findings in preclinical and early phase clinical trials [9,10], statins did not significantly improve clinical outcomes [11,12]. When secondary endpoints were analysed, rosuvastatin was associated with a small decrease in liver and renal failure-free days [13].…”