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* Horizontal Medical Research Organization, Graduate School of Medicine, Kyoto University, Kyoto, Japan;
Department of Internal Medicine, Respiratory Division, Hyogo College of Medicine;
Department of Internal Medicine, Hyogo Prefectural Tsukaguchi Hospital, Hyogo, Japan; and
Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Pulmonary fibrosis in humans can occur as a result of a large number of conditions. In idiopathic pulmonary fibrosis (IPF), pulmonary function becomes progressively compromised resulting in a high mortality rate. Currently there are no proven effective treatments for IPF. We have recently reported that IL-6 and TGF-
1 plays an important role in proliferation and differentiation of lung fibroblasts, and all-trans-retinoic acid (ATRA) prevented bleomycin-induced lung fibrosis through the inhibition of these cytokines. Thalidomide (Thal) has been used in the treatment of multiple myeloma through the inhibitory effect on IL-6-dependent cell growth and angiogenesis. In this study, we examined the preventive effect of Thal on bleomycin-induced pulmonary fibrosis in mice. We performed histological examinations and quantitative measurements of IL-6, TGF-1, collagen type I
1 (COL1A1), vascular endothelial growth factor (VEGF), angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) in bleomycin-treated mouse lung tissues with or without the administration of Thal. Thal histologically ameliorated bleomycin-induced fibrosis in mouse lung tissues. Thal decreased the expressions of IL-6, TGF-1, VEGF, Ang-1 Ang-2, and COL1A1 mRNA in mouse lung tissues. In addition, Thal inhibited angiogenesis in the lung. In vitro studies disclosed that Thal reduced 1) production of IL-6, TGF-1, VEGF, Ang-1, and collagen synthesis from human lung fibroblasts, and 2) both IL-6-dependent proliferation and TGF-1-dependent transdifferentiation of the cells, which could be the mechanism underlying the preventive effect of Thal on pulmonary fibrosis. These data may provide a rationale to explore clinical use of Thal for the prevention of pulmonary fibrosis.
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1 This study was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology and the Special Coordination Funds for Promoting Science and Technology.
2 Address correspondence and reprint requests to Dr. Chiharu Tabata, Department of Internal Medicine, Respiratory Division, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, Japan. E-mail address: ctabata{at}hyo-med.ac.jp
3 Abbreviations used in this paper: IPF, idiopathic pulmonary fibrosis; PKC, protein kinase C; ATRA, all-trans-retinoic acid; Thal, thalidomide; COL1A1, collagen type I1; VEGF, vascular endothelial growth factor; Ang-1, angiopoietin-1; Ang-2, angiopoietin-2; CMC, carboxymethylcellulose; -SMA, smooth muscle actin.
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  P. Rogliani, M. Mura, M. Assunta Porretta, and C. Saltini Review: New perspectives in the treatment of idiopathic pulmonary fibrosis Therapeutic Advances in Respiratory Disease, April 1, 2008; 2(2): 75 - 93. [Abstract] [PDF]
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