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

Saeko Takahashi, Hidetoshi Nakamura, Makoto Seki, Yoshiki Shiraishi, Miyuki Yamamoto, Momoyo Furuuchi, Takahiro Nakajima, Shuko Tsujimura, Toru Shirahata, Miho Nakamura, Naoto Minematsu, Motohiro Yamasaki, Hiroki Tateno, Akitoshi Ishizaka

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Abstract

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.

Original languageEnglish
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume294
Issue number5
DOIs
Publication statusPublished - 2008 May

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Alveolar Epithelial Cells
Pulmonary Emphysema
Simvastatin
Pancreatic Elastase
Cell Proliferation
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Bronchoalveolar Lavage Fluid
Proliferating Cell Nuclear Antigen
Anti-Inflammatory Agents
Endothelial Cells
Nitric Oxide Synthase Type III
Emphysema
Therapeutic Uses

Keywords

  • Endothelial nitric oxide synthase
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology
  • Physiology

Cite this

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

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 294, No. 5, 05.2008.

Research output: Contribution to journalArticle

Takahashi, S, Nakamura, H, Seki, M, Shiraishi, Y, Yamamoto, M, Furuuchi, M, Nakajima, T, Tsujimura, S, Shirahata, T, Nakamura, M, Minematsu, N, Yamasaki, M, Tateno, H & Ishizaka, A 2008, 'Reversal of elastase-induced pulmonary emphysema and promotion of alveolar epithelial cell proliferation by simvastatin in mice', American Journal of Physiology - Lung Cellular and Molecular Physiology, vol. 294, no. 5. https://doi.org/10.1152/ajplung.00238.2007
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. / Reversal of elastase-induced pulmonary emphysema and promotion of alveolar epithelial cell proliferation by simvastatin in mice. In: American Journal of Physiology - Lung Cellular and Molecular Physiology. 2008 ; Vol. 294, No. 5.
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abstract = "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.",
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