RT Journal Article
SR Electronic
T1 Successful Treatment of Acute Lung Injury with Pitavastatin in Septic Mice: Potential Role of Glucocorticoid Receptor Expression in Alveolar Macrophages
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 381
OP 390
DO 10.1124/jpet.110.171462
VO 336
IS 2
A1 Ken-ichi Takano
A1 Seiji Yamamoto
A1 Kengo Tomita
A1 Michinori Takashina
A1 Hiroki Yokoo
A1 Naoyuki Matsuda
A1 Yasuo Takano
A1 Yuichi Hattori
YR 2011
UL http://jpet.aspetjournals.org/content/336/2/381.abstract
AB There is growing evidence that the HMG-CoA reductase inhibitors (statins) provide some of the beneficial effects that are 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 per day of pitavastatin was initiated 4 days before surgery and was maintained for life support 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. Although plasma cortisol showed a sharp rise, glucocorticoid receptor (GCR) expression in the lungs was strikingly reduced after the onset of CLP-induced sepsis. It is noteworthy that 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.