Simvastatin Inhibits Cigarette Smoking-Induced Emphysema and Pulmonary Hypertension in Rat Lungs

Am J Respir Crit Care Med. 2005 Oct 15;172(8):987-93. doi: 10.1164/rccm.200501-041OC. Epub 2005 Jul 7.

Abstract

Rationale: In cigarette smoking-induced chronic obstructive pulmonary disease, structural and functional derangements are characterized by parenchymal destruction and pulmonary hypertension. Statins are 3-hydroxy-3-methyl-glutaryl-coenzyme-A reductase inhibitors that have been used as lipid-lowering agents. These drugs also have additional pharmacologic properties, including antiinflammation, scavenging reactive oxygen species, restoring endothelial function, and antithrombogenesis, all of which can counteract the harmful effects of cigarette smoking.

Objective: We performed assays to determine whether simvastatin could attenuate lung damage induced by chronic cigarette smoking in rats.

Methods: In Sprague-Dawley rats exposed to cigarette smoke for 16 weeks, morphologic changes in the lungs and pulmonary arterial pressure were examined.

Main results: Simvastatin inhibited lung parenchymal destruction and development of pulmonary hypertension, and also inhibited peribronchial and perivascular infiltration of inflammatory cells and induction of matrix metalloproteinase-9 activity in lung tissue. Simvastatin additionally prevented pulmonary vascular remodeling and the changes in endothelial nitric oxide synthase expression induced by smoking. In human lung microvascular endothelial cells, simvastatin increased expression of endothelial nitric oxide synthase mRNA.

Conclusions: Simvastatin ameliorated the structural and functional derangements of the lungs caused by cigarette smoking, partly by suppressing inflammation and matrix metalloproteinase-9 induction and preventing pulmonary vascular abnormality. These findings indicate that statins may play a role in the treatment of cigarette smoking-induced chronic obstructive pulmonary disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Analysis of Variance
  • Animals
  • Biopsy
  • Chronic Disease
  • Disease Models, Animal
  • Drug Evaluation, Preclinical
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use*
  • Hypertension, Pulmonary / etiology
  • Hypertension, Pulmonary / prevention & control*
  • Inflammation
  • Male
  • Matrix Metalloproteinase 2 / analysis
  • Matrix Metalloproteinase 2 / drug effects
  • Matrix Metalloproteinase 2 / immunology
  • Matrix Metalloproteinase 3 / analysis
  • Matrix Metalloproteinase 3 / drug effects
  • Matrix Metalloproteinase 3 / immunology
  • Nitric Oxide Synthase / drug effects
  • Nitric Oxide Synthase / immunology
  • Pulmonary Artery / drug effects
  • Pulmonary Artery / immunology
  • Pulmonary Artery / pathology
  • Pulmonary Emphysema / etiology
  • Pulmonary Emphysema / prevention & control*
  • Rats
  • Rats, Sprague-Dawley
  • Risk Factors
  • Simvastatin / pharmacology
  • Simvastatin / therapeutic use*
  • Smoking / adverse effects*
  • Smoking / drug therapy
  • Smoking / immunology
  • Smoking / metabolism
  • Smoking / pathology
  • Time Factors

Substances

  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Simvastatin
  • Nitric Oxide Synthase
  • Matrix Metalloproteinase 3
  • Matrix Metalloproteinase 2