Abstract

There is growing evidence that the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) provide some of beneficial effects independent of their lipid-lowering effects. Recent animal experiments and clinical trials suggest that statin use may limit the development of sepsis and associated systemic inflammation. The aim of this study was to explore the potential role of statins in the prevention treatment of sepsis-induced acute lung injury (ALI). Mice were rendered septic by cecal ligation and puncture (CLP). An intraperitoneal injection of 3 mg/kg/day pitavastatin was initiated 4 days before surgery and was maintained for life afterward, which significantly improved the survival of CLP mice. Treatment with pitavastatin prevented the ALI development in CLP mice, as indicated by the findings that severe hypoxemia, increased pulmonary vascular permeability, and histological lung damage, including inflammatory cell infiltrate, were greatly remedied. This was associated with down-regulation of increased activity of nuclear factor-κB (NF-κB) in septic lungs. While plasma cortisol showed a sharp rise, glucocorticoid receptors (GCR) expression in the lungs was strikingly reduced after the onset of CLP-induced sepsis. Importantly, pitavastatin increased GCR expression with an increase in alveolar macrophages, in which GCRs are localized, without modifying the sepsis-associated rise in plasma cortisol. These results confirm significant protection by pitavastatin on septic ALI and demonstrate that down-regulated NF-κB activation associated with the GCR expression increase consequent to the increased number of alveolar macrophages may explain, in part, the mechanisms responsible for favorable effects of statins on the ALI management.