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Published ahead of print on July 7, 2005, doi:10.1164/rccm.200501-041OC

Am. J. Respir. Crit. Care Med., Volume 172, Number 8, October 2005, 987-993

A more recent version of this article appeared on October 15, 2005
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Submitted on January 10, 2005
Accepted on July 1, 2005

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

Ji-Hyun Lee1, Dong-Soon Lee2, Eun-Kyung Kim1, Kang-Hyeon Choe3, Yeon-Mock Oh4, Tae-Sun Shim5, Sang-Eun Kim6, Yun-Song Lee6, and Sang-Do Lee4*

1 Division of Pulmonary and Critical Care Medicine, Pochon CHA University, Seongnam, Korea, 2 National Research Laboratory, Department of Laboratory Medicine, College of Medicine Seoul National University, Seoul, Korea, 3 Division of Pulmonary and Critical Care Medicine, Chungbuk National University, Cheongju, Korea, 4 Division of Pulmonary and Critical Care Medicine, College of Medicine University of Ulsan, Asan Medical Center, Seoul, Korea; Clinical Research Center for Chronic Obstructive Airway Diseases, 5 Division of Pulmonary and Critical Care Medicine, College of Medicine University of Ulsan, Asan Medical Center, Seoul, Korea, 6 Department of Molecular and Cellular Biology, Respiratory Research Center, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, Korea

* To whom correspondence should be addressed. E-mail: sdlee{at}amc.seoul.kr.

Rationale: In cigarette smoking-induced chronic obstructive pulmonary disease (COPD), structural and functional derangements are characterized by parenchymal destruction and pulmonary hypertension. Statins are HMG-CoA reductase inhibitors that have been employed as lipid lowering agents. These drugs also have additional pharmacological properties, including anti-inflammation, scavenging reactive oxygen species, restoring endothelial function, and anti-thrombogenesis, all of which can counteract the harmful effects of cigarette smoking. Objective: We assayed 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, morphological 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 metalloproteinases-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 metalloproteinases-9 induction and preventing pulmonary vascular abnormality. These findings indicate that statins may play a role in the treatment of cigarette smoking-induced COPD.
Key words: statin, smoking, emphysema, pulmonary hypertension




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