Submitted on June 20, 2007
Accepted on February 24, 2008
Reversal of elastase-induced pulmonary emphysema and promotion of alveolar epithelial cell proliferation by simvastatin in mice
Saeko Takahashi1, Hidetoshi Nakamura2*, Makoto Seki3, Yoshiki Shiraishi1, Miyuki Yamamoto4, Momoyo Furuuchi1, Takahiro Nakajima1, Shuko Tsujimura1, Toru Shirahata1, Miho Nakamura1, Naoto Minematsu1, Motohiro Yamasaki3, Hiroki Tateno1, and Akitoshi Ishizaka1
1 Division of Pulmonary Medicine, Department of Medicine, Keio University, Tokyo, Japan
2 Department of Medicine, Tokyo Electric Power Company Hospital, Tokyo, Japan
3 Research & Development Division, Mitsubishi Pharma Corporation, Yokohama, Japan
4 Division of Pulmonary Medicine, Department of Medicine, Keio University, Japan
* To whom correspondence should be addressed. E-mail: hnakamura{at}cpnet.med.keio.ac.jp.
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 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 weeks. A 21% decrease in Lm on day 7 was observed in SS+ compared with SS- group. Anti-inflammatory effects of SS were observed as a decrease in % neutrophils up to day 3, and in hydroxyproline concentration on day 3, in broncho-alveolar lavage fluid (BALF). SS also increased the number of proliferating cell nuclear antigen (PCNA)-positive alveolar epithelial cells between day 3 and 14. To confirm the role of statins in promoting proliferation of alveolar cells, mice were treated with SS (SS+) versus PBS (SS-) for 12 days, starting 3 weeks after elastase administration. After SS treatment, Lm decreased by 52% and PCNA-positive alveolar epithelial cells increased compared with SS- group. Concentrations of vascular endothelial growth factor in BALF and endothelial NO synthase protein expression in pulmonary vessels tended to be higher in SS+ than in SS- group in this protocol. In conclusion, SS inhibited the development of elastase-induced pulmonary emphysema in mice. This therapeutic effect was not only due to anti-inflammation but also to the promotion of alveolar epithelial cell regeneration, partly mediated by restoring endothelial cell functions.
