Reversal of elastase-induced pulmonary emphysema and promotion of alveolar epithelial cell proliferation by simvastatin in mice

• Published in: American journal of physiology. Lung cellular and molecular physiology Vol. 294; no. 5; pp. L882 - L890
• Main Authors: Takahashi, Saeko, Nakamura, Hidetoshi, Seki, Makoto, Shiraishi, Yoshiki, Yamamoto, Miyuki, Furuuchi, Momoyo, Nakajima, Takahiro, Tsujimura, Shuko, Shirahata, Toru, Nakamura, Miho, Minematsu, Naoto, Yamasaki, Motohiro, Tateno, Hiroki, Ishizaka, Akitoshi
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.05.2008
• Subjects: Airway management; Animals; Bronchoalveolar Lavage Fluid; Cell Division - drug effects; Cells; Chemokine CXCL2 - metabolism; Chemokines - metabolism; Cholesterol; Collagen - metabolism; Disease Models, Animal; Dose-Response Relationship, Drug; Emphysema; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Hydroxyproline - metabolism; Lungs; Male; Mice; Mice, Inbred C57BL; Neutrophils - pathology; Nitric oxide; Nitric Oxide Synthase Type II - genetics; Nitric Oxide Synthase Type II - metabolism; Nitric Oxide Synthase Type III; Pancreatic Elastase; Proliferating Cell Nuclear Antigen - metabolism; Pulmonary Alveoli - drug effects; Pulmonary Alveoli - metabolism; Pulmonary Alveoli - pathology; Pulmonary Emphysema - chemically induced; Pulmonary Emphysema - drug therapy; Pulmonary Emphysema - pathology; Recovery of Function - drug effects; Respiratory Mucosa - drug effects; Respiratory Mucosa - metabolism; Respiratory Mucosa - pathology; Reverse Transcriptase Polymerase Chain Reaction; Rodents; Simvastatin - pharmacology; Tumor Necrosis Factor-alpha - metabolism; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00238.2007

1 Division of Pulmonary Medicine, Department of Medicine, Keio University and 2 Department of Medicine, Tokyo Electric Power Company Hospital, Tokyo; and 3 Research and Development Division, Mitsubishi Pharma Corporation, Yokohama, Japan Submitted 20 June 2007 ; accepted in final form 24 February 2008 Besides lowering cholesterol, statins exert multiple effects, such as anti-inflammatory activity and improvement of endothelial cell function. We examined whether simvastatin (SS) protects against the development of elastase-induced pulmonary emphysema in mice by using mean linear intercepts of alveoli (Lm) as a morphometric parameter of emphysema. After injection of intratracheal elastase on day 0 , C57BL/6 mice were treated daily with SS (SS+ group) or PBS (SS– group) for 2 wk. A 21% decrease in Lm on day 7 was observed in the SS+ group vs. the SS– group. Anti-inflammatory effects of SS were observed as a decrease in percentage of neutrophils up to day 3 , and in hydroxyproline concentration on day 3 , in bronchoalveolar lavage fluid (BALF). SS also increased the number of proliferating cell nuclear antigen (PCNA)-positive alveolar epithelial cells between days 3 and 14 . To confirm the role of statins in promoting proliferation of alveolar cells, mice were treated with SS (SS+) vs. PBS (SS–) for 12 days, starting 3 wk after elastase administration. After SS treatment, Lm decreased by 52% and PCNA-positive alveolar epithelial cells increased compared with the SS– group. Concentrations of vascular endothelial growth factor in BALF and endothelial nitric oxide synthase protein expression in pulmonary vessels tended to be higher in the SS+ group vs. the SS– group in this protocol. In conclusion, SS inhibited the development of elastase-induced pulmonary emphysema in mice. This therapeutic effect was due not only to anti-inflammation but also to the promotion of alveolar epithelial cell regeneration, partly mediated by restoring endothelial cell functions. vascular endothelial growth factor; endothelial nitric oxide synthase Address for reprint requests and other correspondence: H. Nakamura, Dept. of Medicine, Tokyo Electric Power Company Hospital, 9-2 Shinanomachi, Shinjuku-ku, Tokyo 160-0016, Japan (e-mail: hnakamura{at}cpnet.med.keio.ac.jp )