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Interferon-ß Inhibits Bleomycin-Induced Lung Fibrosis by Decreasing Transforming Growth Factor-ß and Thrombospondin

Fourth Department of Internal Medicine, Nippon Medical School, and First Department of Internal Medicine, Nihon University School of Medicine, Tokyo; Pharmaceutical Research Laboratories, Toray Industries, Inc.; and Department of BioResearch, Kamakura TechnoScience, Inc., Kanagawa, Japan

Address correspondence to: Arata Azuma, M.D., Ph.D., Fourth Department of Internal Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113, Japan. E-mail: a-azuma{at}nms.ac.jp

Pulmonary fibrosis is the result of abnormal processes of repair that occur after lung injury. Transforming growth factor (TGF)-ß is a key molecule in the progression of pulmonary fibrosis. Although clinical use of interferon (IFN)-ß did not improve survival in patients with idiopathic pulmonary fibrosis, because some preclinical studies have suggested that IFN-ß is a potent inhibitor of fibrogenesis, beneficial effects of IFN-ß have been expected. We therefore attempted to determine effects of IFN-ß and investigated the mechanism of action of IFN-ß in bleomycin-induced pulmonary fibrosis. Bleomycin at Day 0 and IFN-ß for 4 wk were administered intravenously to ICR mice. At 28 d after bleomycin injection, histologic and chemical analysis was performed for evaluation of effects of IFN-ß. Tissue distribution and amounts of TGF-ß1 and thrombospondin (TSP)-1/2 were analyzed. IFN-ß attenuated prolylhydroxylase activity, resulting in inhibition of pulmonary fibrosis. Bleomycin-induced increase in TGF-ß1 in epithelial cells and extracellular matrix was attenuated by IFN-ß. TSP-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 IFN-ß is inhibition of TGF-ß and its activation via decrease in TSP-1/2 in lung tissue and change in location of TSP-1/2 from platelets to foamy cells.

Key Words: interstitial pneumonia • TGF-ß • thrombospondin • interferon-ß • bleomycin

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