Interferon-{beta} inhibits bleomycin-induced lung fibrosis by decreasing transforming growth factor-{beta} and thrombospondin.
Pulmonary fibrosis is the result of abnormal processes of repair that occur after lung injury. Transforming growth factor (TGF)-beta is a key molecule in the progression of pulmonary fibrosis. Although clinical use of interferon (IFN)-beta did not improve survival in patients with idiopathic pulmonary fibrosis, because some preclinical studies have suggested that IFN-beta is a potent inhibitor of fibrogenesis, beneficial effects of IFN-beta have been expected. We therefore attempted to determine effects of IFN-beta and investigated the mechanism of action of IFN-beta in bleomycin-induced pulmonary fibrosis. Bleomycin at Day 0 and IFN-beta 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-beta. Tissue distribution and amounts of TGF-beta1 and thrombospondin (TSP)-1/2 were analyzed. IFN-beta attenuated prolylhydroxylase activity, resulting in inhibition of pulmonary fibrosis. Bleomycin-induced increase in TGF-beta1 in epithelial cells and extracellular matrix was attenuated by IFN-beta. 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-beta is inhibition of TGF-beta 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.
Azuma
Arata
A
Fourth Department of Internal Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113, Japan. a-azuma@nms.ac.jp
Li
Ying Ji
YJ
Abe
Shinji
S
Usuki
Jiro
J
Matsuda
Kuniko
K
Henmi
Satoshi
S
Miyauchi
Yasushi
Y
Ueda
Kohei
K
Izawa
Akiko
A
Sone
Saburo
S
Hashimoto
Shu
S
Kudoh
Shoji
S
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage*; D001761:Bleomycin / Q000008:administration & dosage*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005109:Extracellular Matrix / Q000378:metabolism; D005487:Foam Cells / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D016899:Interferon-beta / Q000008:administration & dosage*; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D019700:Thrombospondin 1 / Q000378:metabolism*; D019699:Thrombospondins / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D000099262:Thrombospondin 2
D000903:Antibiotics, Antineoplastic; D001761:Bleomycin; D016899:Interferon-beta; D011393:Procollagen-Proline Dioxygenase; D019700:Thrombospondin 1; D019699:Thrombospondins; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000099262:Thrombospondin 2; C508961:Tgfb1 protein, mouse