Long-term simvastatin attenuates lung injury and oxidative stress in murine acute lung injury models induced by oleic Acid and endotoxin

Respir Care. 2011 Aug;56(8):1156-63. doi: 10.4187/respcare.00770. Epub 2011 Mar 9.

Abstract

Background: 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors have several pleiotropic effects, including anti-inflammatory properties, and are reported to improve endothelial functions. Pathophysiologically, acute lung injury (ALI) is caused by a severe inflammatory response and endothelial dysfunction.

Objective: To investigate the effects of simvastatin (an HMG-CoA reductase inhibitor) on oxidative stress and lung histopathology in 2 murine models of ALI, induced by oleic acid and endotoxin.

Methods: The mice were randomly divided into 2 groups: one received 2 mg/kg/d intraperitoneal simvastatin for 15 days. Then the groups were further divided into 3, which received saline, oleic acid, or endotoxin. Four hours after inducing ALI we obtained lung samples for histopathology analysis, myeloperoxidase, glutathione, and malondialdehyde measurement, and blood samples for malondialdehyde measurement.

Results: Endotoxin and oleic acid lung injury increased tissue myeloperoxidase (P = .009 for both), decreased tissue glutathione (P = .02 and P = .009, respectively), and increased tissue malondialdehyde (P = .009 for both), compared to the control group. Simvastatin decreased myeloperoxidase only in the oleic acid group (P = .01). Simvastatin increased glutathione (P = .005 and P = .003, respectively) and lowered malondialdehyde in both the endotoxin and oleic acid groups (P = .003 for both). Histopathology revealed that simvastatin protected the lung tissue in both ALI models, but the protection was greater in the endotoxin group.

Conclusions: Pretreatment with simvastatin decreased the severity of ALI in oleic acid and endotoxin ALI models, by decreasing inflammation and oxidative stress.

Publication types

  • Comparative Study

MeSH terms

  • Acute Lung Injury / chemically induced
  • Acute Lung Injury / drug therapy
  • Acute Lung Injury / metabolism*
  • Animals
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Endotoxins / toxicity
  • Follow-Up Studies
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / administration & dosage*
  • Injections, Intraperitoneal
  • Mice
  • Oleic Acid / toxicity
  • Oxidative Stress / drug effects*
  • Simvastatin / administration & dosage*
  • Time Factors

Substances

  • Endotoxins
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Oleic Acid
  • Simvastatin