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Published ahead of print on November 19, 2004, doi:10.1165/rcmb.2003-0374OC

Am. J. Respir. Cell Mol. Biol., Volume 32, Number 2, February 2005, 93-98

A more recent version of this article appeared on February 1, 2005
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Submitted on October 22, 2003
Revised on November 16, 2004

Interferon-{beta} Inhibits Bleomycin-Induced Lung Fibrosis by Decreasing TGF-{beta} and Thrombospondin

Arata Azuma1*, Ying Ji Li1, Shinji Abe1, Jiro Usuki1, Kuniko Matsuda1, Satoshi Henmi2, Yasushi Miyauchi3, Kohei Ueda3, Akiko Izawa2, Saburo Sone2, Shu Hashimoto4, and Shoji Kudoh1

1 Fourth Department of Internal Medicine, Nippon Medical School, Tokyo, Japan, 2 Pharmaceutical Research Laboratories, Toray Industries, Inc., Kanagawa, Japan, 3 Department of Bio Research, Kamakura Techno Science, Kanagawa, Japan, 4 First Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan

* To whom correspondence should be addressed. E-mail: a-azuma{at}nms.ac.jp.

Pulmonary fibrosis is the result of abnormal processes of repair that occur following lung injury. TGF-{beta} is a key molecule in the progression of pulmonary fibrosis. Although clinical use of interferon-{beta} did not improve survival in patients with idiopathic pulmonary fibrosis, since some preclinical studies have suggested that interferon-{beta} is a potent inhibitor of fibrogenesis, beneficial effects of interferon-{beta} have been expected. We therefore attempted to determine effects of interferon-{beta} and investigated the mechanism of action of interferon-{beta} in bleomycin-induced pulmonary fibrosis. Bleomycin at day 0 and interferon-{beta} for 4 weeks were administered intravenously to ICR mice. At 28 days after bleomycin injection, histological and chemical analysis was performed for evaluation of effects of interferon-{beta}. Tissue distribution and amounts of TGF-{beta}1 and thrombospondin-1/2 were analyzed. Interferon-{beta} attenuated prolylhydroxylase activity, resulting in inhibition of pulmonary fibrosis. Bleomycin-induced increase in TGF-{beta}1 in epithelial cells and extracellular matrix was attenuated by interferon-{beta}. Thrombospondin-1/2 was limited in platelets of control mice, but was present in foamy cells in fibrotic regions induced by bleomycin. These findings suggest that the antifibrotic effect of interferon-{beta} is inhibition of TGF-{beta} and its activation via decrease in thrombospondin-1/2 in lung tissue and change in location of thrombospondin-1/2 from platelets to foamy cells.




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