Dasatinib Suppresses TGFβ-Mediated Epithelial-Mesenchymal Transition in Alveolar Epithelial Cells and Inhibits Pulmonary Fibrosis

被引：24

作者：

Kanemaru, Ryota ^{[1
,2
]}

Takahashi, Fumiyuki ^{[1
,2
]}

Kato, Motoyasu ^{[1
,2
]}

Mitsuishi, Yoichiro ^{[1
,2
]}

Tajima, Ken ^{[1
,2
]}

Ihara, Hiroaki ^{[1
,2
]}

Hidayat, Moulid ^{[1
,2
]}

Wirawan, Aditya ^{[1
,2
]}

Koinuma, Yoshika ^{[1
,2
]}

Hayakawa, Daisuke ^{[1
,2
]}

Yagishita, Shigehiro ^{[1
,2
]}

Ko, Ryo ^{[1
,2
]}

Sato, Tadashi ^{[1
,2
]}

Harada, Norihiro ^{[1
,2
]}

Kodama, Yuzo ^{[1
,2
]}

Nurwidya, Fariz ^{[1
,2
]}

Sasaki, Shinichi ^{[1
,2
]}

Niwa, Shin-ichiro ^{[4
]}

Takahashi, Kazuhisa ^{[1
,2
,3
]}

机构：

[1] Juntendo Univ, Grad Sch Med, Dept Resp Med, Bunkyo Ku, 2-1-1 Hongo, Tokyo 1138421, Japan

[2] Juntendo Univ, Grad Sch Med, Res Inst Dis Old Ages, Tokyo, Japan

[3] Juntendo Univ, Grad Sch Med, Leading Ctr Dev & Res Canc Med, Tokyo, Japan

[4] Link Genom Inc, Tokyo, Japan

来源：

LUNG | 2018年 / 196卷 / 05期

关键词：

Dasatinib; Pulmonary fibrosis; Epithelial mesenchymal transition; TGF beta; USUAL INTERSTITIAL PNEUMONIA; CHRONIC MYELOID-LEUKEMIA; FIBROBLASTIC FOCI; MYOFIBROBLAST DIFFERENTIATION; LUNG-CANCER; RESISTANCE; KINASE; EMT; PIRFENIDONE; MECHANISM;

D O I：

10.1007/s00408-018-0134-6

中图分类号：

R56 [呼吸系及胸部疾病];

学科分类号：

摘要：

Transforming growth factor beta (TGF beta)-mediated epithelial-mesenchymal transition (EMT) of alveolar epithelial cells contributes to pulmonary fibrosis. Dasatinib (DAS), a potent and broad-spectrum tyrosine kinase inhibitor, has been widely studied as an anti-cancer agent. However, the therapeutic application of DAS for pulmonary fibrosis has not been clarified. Our purpose here is to investigate the effect of DAS on TGF beta 1-induced EMT in human alveolar and bronchial epithelial cells in vitro and to evaluate the efficacy of DAS on lung fibrosis in vivo. TGF beta 1-stimulated human alveolar epithelial (A549) and bronchial epithelial (BEAS-2B) cells were treated with or without DAS in vitro. Murine pulmonary fibrosis model was generated by injection of bleomycin (BLM). A549 and BEAS-2B cells exposed to TGF beta 1 underwent EMT, as indicated by downregulation of epithelial protein E-cadherin and induction of the mesenchymal proteins, fibronectin and type I and type IV collagen. These effects were dramatically suppressed by DAS treatment, which also prevented Smad2 and Smad3 phosphorylation. DAS inhibited TGF beta 1-induced cell motility and migration. Furthermore, DAS administration significantly attenuated lung fibrosis in mice by histological analysis. Treatment with DAS also significantly reduced the levels of collagen and fibronectin and phosphorylation of Smad2 in the lung tissues of the murine model. These findings suggest that DAS inhibited TGF beta-mediated EMT of alveolar and bronchial epithelial cells and attenuated BLM-induced lung fibrosis in mice by suppressing the TGF beta/Smad pathway. DAS may be a promising and novel anti-fibrotic agent for preventing lung fibrosis.

引用

页码：531 / 541

页数：11

共 33 条

[1] Dasatinib inhibits TGFβ-induced myofibroblast differentiation through Src-SRF Pathway [J].