Anti-fibrotic effect of thalidomide through inhibiting TGF-beta-induced ERK1/2 pathways in bleomycin-induced lung fibrosis in mice.
OBJECTIVE
This study is designed to confirm the anti-fibrotic effect of thalidomide on bleomycin-induced lung fibrosis in a mouse model and to identify whether this anti-fibrotic effect is associated with inhibition of the transforming growth factor-beta (TGF-beta)-induced extracellular signal-regulated kinase1/2 (ERK1/2).


METHODS
C57BL/6 female mice were administered blomycin sulfate. In cultured human lung fibroblasts, expressions of type I collagen, fibronectin, and either TGF-beta or IL-6 were measured after thalidomide treatment by reverse transcription-polymerase chain reaction (RT-PCR). Expressions of ERK1/2, type I collagen, fibronectin, and TGF-beta1 from lung tissues of blomycin-induced mice and from mouse lung fibroblasts were evaluated using RT-PCR and western blotting.


RESULTS
Thalidomide administration significantly inhibits TGF-beta1 mRNA expression in a dose-dependant manner following administration of IL-6 and IL-6R. In the analysis of BAL fluids, total BAL inflammatory cell counts, TGF-beta1, and IL-6 levels in thalidomide-treated mice were significantly reduced when compared with bleomycin-treated mice (p < 0.01, p < 0.01, and p < 0.001, respectively). Thalidomide inhibited total ERK1/2 and phospho-ERK1/2 expression after TGF-beta1 stimulation in the RT-PCR and western blotting.


CONCLUSIONS
The results of our study suggest that the anti-fibrotic effect of thalidomide on lung fibrosis may be related to suppression of the TGF-beta1-induced ERK1/2 signaling pathway.
Choe
Jung-Yoon
JY
Department of Internal Medicine, Catholic University of Daegu School of Medicine, 3056-6 Daemyung 4-Dong, Namgu, Daegu, 705-718, South Korea.
Jung
Hyun-Joo
HJ
Park
Ki-Yeun
KY
Kum
Yoon-Seup
YS
Song
Gwan Gyu
GG
Hyun
Dae-Sung
DS
Park
Sung-Hoon
SH
Kim
Seong-Kyu
SK
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D001761:Bleomycin; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013792:Thalidomide / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D015850:Interleukin-6; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; D013792:Thalidomide; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3