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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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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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