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

Chronic obstructive pulmonary disease (COPD) is defined as a disease associated with an abnormal inflammatory response of the lungs to noxious particles or gas (1). Cigarette smoking is the most important risk factor for the development of COPD. Chronic smoke exposure causes airway and lung parenchymal inflammation, which is characterized by increased numbers of macrophages, lymphocytes, neutrophils, and/or eosinophils (2). Several kinds of proteases, including neutrophil elastase, macrophage elastase, matrix metalloproteinases (MMPs), and cathepsins, from these inflammatory cells may contribute to alveolar destruction and result in pulmonary emphysema in chronic cigarette smokers (3-7). In addition, reactive oxygen species produced by cigarette smoke (8) or inflammatory cells, including activated lung macrophages and infiltrating neutrophils (9), may contribute to emphysematous changes, in that massive and continuous oxidative stress may overwhelm the antioxidant capacity of lung tissue, thereby causing damage.

In addition to causing structural damage of lung tissue, cigarette smoking has been shown to induce prominent pulmonary vascular changes characterized by endothelial dysfunction and vascular remodeling, which lead to pulmonary hypertension (10-13). Suppression of endothelial nitric oxide (NO) production is suggested as a potential cause of the endothelial dysfunction and impaired vasodilation in humans (11), although chronic exposure to cigarette smoke oppositely induced endothelial NO synthase (eNOS) expression in guinea pig pulmonary arteries (14). In addition, pulmonary vascular remodeling, characterized by intimal and medial thickening with proliferation of smooth muscle cells and deposition of elastic and collagen fibers in pulmonary arteries, may be an underlying mechanism for pulmonary hypertension in COPD (12). In smoking-induced structural and functional derangements of pulmonary circulation, potential pathologic causative factors may include direct oxidative damage by cigarette smoke products and subsequent inflammation, as well as exposure to chronic hypoxia (13). Furthermore, a tendency toward hypercoagulation induced by cigarette smoking may be an additional factor contributing to pulmonary hypertension (15).

Statins are 3-hydroxy-3-methyl-glutaryl-coenzyme-A (HMG-CoA) reductase inhibitors that have been used clinically as lipid-lowering agents. Statins, however, have additional pleiotropic pharmacologic properties, including antiinflammatory, antioxidant, antithrombogenic, and vascular function-restoring actions (16). Interestingly, all of these additional actions may counteract the harmful effects of cigarette smoking and chronic inflammation. We therefore performed assays to determine the beneficial effects of simvastatin on chronic cigarette smoking-induced lung damage, using a rat model. To our knowledge, this study is the first to show that simvastatin ameliorates cigarette smoking-induced structural and functional derangement of the lungs, possibly by reducing inflammatory infiltration, inhibiting MMP-9 induction and preventing pathologic changes in pulmonary vasculature. These findings indicate that statins may be used in the treatment of cigarette smoking-induced COPD.

We submitted abstracts and presented part of this study at the Aspen Lung Conference (Aspen, CO, 2004) and COPD 4 (Birmingham, UK, 2004). This article reports our complete study findings.

METHODS

Smoking Exposure and Treatment Groups

This animal study was approved by the Panel on Laboratory Animal Care of Asan Medical Center. Male Sprague-Dawley rats (Orient, South Korea) were exposed to the smoke of 10 commercial cigarettes (Eighty Eight Lights, South Korea) per day for 16 weeks (17). Rats were divided into four groups: control (CTL), smoking-only (SM), smoking-plus-simvastatin (SMST), and statin-only (ST) groups. Simvastatin, at a dose of 5 mg/kg, was administered orally to rats in the SMST and ST groups once per day for 16 weeks.

Hemodynamic and Histologic Analysis

At the end of the 16 weeks, mean pulmonary arterial pressure (MPAP) was measured by cannulation through the right jugular vein. After the lungs were removed en bloc, the right and left lungs were used for histologic and biochemical analysis, respectively.

In hematoxylin-and-eosin-stained lung sections, average interalveolar septal wall distance (mean linear intercept [MLI]) (18), and alveolar surface-to-volume ratio (S/V) were measured (19). The degree of peribronchial and perivascular inflammation was scored on a subjective scale of 0 (no) to 4 (severe) in a blind manner (20).