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Simvastatin Inhibits Cigarette Smoking–induced Emphysema and Pulmonary Hypertension in Rat Lungs

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, College of Medicine, Pochon CHA University, Seongnam; National Research Laboratory, Department of Laboratory Medicine, College of Medicine, Seoul National University; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Asan Medical Center, College of Medicine, University of Ulsan; Clinical Research Center for Chronic Obstructive Airway Diseases, Seoul; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, College of Medicine, Chungbuk National University, Cheongju; Department of Molecular and Cellular Biology, Respiratory Research Center, Medical Research Institute, Sungkyunkwan University School of Medicine; and Samsung Biomedical Research Institute, Suwon, South Korea

Correspondence and requests for reprints should be addressed to Sang-Do Lee, M.D., Ph.D., Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Asan Medical Center, College of Medicine, University of Ulsan, 388-1 Poongnab-dong, Songpa-gu, Seoul 138-736, South Korea. E-mail: sdlee{at}amc.seoul.kr

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.

Key Words: emphysema • pulmonary hypertension • smoking • statin

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