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Published ahead of print on June 23, 2005, doi:10.1164/rccm.200412-1620OC
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American Journal of Respiratory and Critical Care Medicine Vol 172. pp. 713-720, (2005)
© 2005 American Thoracic Society
doi: 10.1164/rccm.200412-1620OC

Attenuation of Bleomycin-induced Pulmonary Fibrosis by Follistatin

Fumiaki Aoki, Masahiko Kurabayashi, Yoshihisa Hasegawa and Itaru Kojima

Institute for Molecular and Cellular Regulation, Gunma University; Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Maebashi; and School of Veterinary Medicine and Animal Science, Kitasato University, Towada, Japan.

Correspondence and requests for reprints should be addressed to Itaru Kojima, M.D., Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan. E-mail: ikojima{at}showa.gunma-u.ac.jp

Rationale: Activins are members of the transforming growth factor-ß superfamily thought to be involved in repair processes after tissue injury. Objectives: The aim of this study was to clarify whether activin and its antagonist, follistatin, played a significant role in lung injury and fibrosis. Methods and Results: In bleomycin (BLM)-treated rat lung, mRNA for the ßA subunit of activin was upregulated on Days 3 and 7 and decreased gradually thereafter. Immunoreactive activin A was abundantly expressed in macrophages infiltrated in the lung, and was detected in fibroblasts accumulated in the fibrotic area on Day 28. We then administered follistatin, an activin antagonist, to BLM-treated rats. Follistatin significantly reduced the number of macrophages and neutrophils in bronchoalveolar lavage and reduced the protein content. Histologically, follistatin markedly reduced the number of infiltrating cells, ameliorated the destruction of lung architecture on Day 7, and attenuated lung fibrosis on Day 28. The hydroxyproline content was significantly lower in follistatin-treated rats. In cultured lung fibroblasts, production of activin A was augmented by transforming growth factor-ß, and activin antagonist follistatin significantly inhibited transforming growth factor-ß–induced fibroblast activation. These results suggest that activin A was produced in the lung after BLM treatment and promoted acute inflammation and subsequent fibrosis. Conclusions: Follistatin is effective in treating acute lung injury and BLM-induced fibrosis by blocking the actions of activin and transforming growth factor-ß.

Key Words: activin • extracellular matrix • lung • macrophage




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