title: Thalidomide prevents bleomycin-induced pulmonary fibrosis in mice.
abstract: 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-beta(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-beta(1), collagen type Ialpha1 (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-beta(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-beta(1), VEGF, Ang-1, and collagen synthesis from human lung fibroblasts, and 2) both IL-6-dependent proliferation and TGF-beta(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.
authors.affiliation: Horizontal Medical Research Organization, Graduate School of Medicine, Kyoto University, Kyoto, Japan. ctabata@hyo-med.ac.jp
authors.forename: Chiharu
authors.initials: C
authors.lastname: Tabata
authors.forename: Rie
authors.initials: R
authors.lastname: Tabata
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Kadokawa
authors.forename: Shigeo
authors.initials: S
authors.lastname: Hisamori
authors.forename: Meiko
authors.initials: M
authors.lastname: Takahashi
authors.forename: Michiaki
authors.initials: M
authors.lastname: Mishima
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakano
authors.forename: Hajime
authors.initials: H
authors.lastname: Kubo
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000037:antagonists & inhibitors / Q000633:toxicity*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002461:Cell Line, Transformed; D024042:Collagen Type I / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D000090602:Collagen Type I, alpha 1 Chain; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000517:prevention & control; D011506:Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D012259:Ribonuclease, Pancreatic; D013792:Thalidomide / Q000494:pharmacology* / Q000627:therapeutic use; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors
chemical_list: D001761:Bleomycin; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D015850:Interleukin-6; D011506:Proteins; D012333:RNA, Messenger; D012259:Ribonuclease, Pancreatic; D013792:Thalidomide; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; D000093242:Interleukin-6 Inhibitors; C046366:angiogenin