Pirfenidone attenuates lung fibrotic fibroblast responses to transforming growth factor-β1

被引：92

作者：

Jin, Jin ^{[1
,2
,3
,4
]}

Togo, Shinsaku ^{[2
,3
,4
,9
,10
]}

Kadoya, Kotaro ^{[2
,3
,4
]}

Tulafu, Miniwan ^{[2
,3
,4
]}

Namba, Yukiko ^{[2
,3
,4
,5
]}

Iwai, Moe ^{[2
,3
,4
]}

Watanabe, Junko ^{[2
,3
,4
]}

Nagahama, Kumi ^{[2
,3
,4
]}

Okabe, Takahiro ^{[2
,3
,4
]}

Hidayat, Moulid ^{[2
,3
,4
]}

Kodama, Yuzo ^{[2
,3
,4
]}

Kitamura, Hideya ^{[5
]}

Ogura, Takashi ^{[5
]}

Kitamura, Norikazu ^{[6
]}

Ikeo, Kazuho ^{[6
,7
]}

Sasaki, Shinichi ^{[8
]}

Tominaga, Shigeru ^{[8
]}

Takahashi, Kazuhisa ^{[2
,3
,4
]}

机构：

[1] Beijing Hosp, Dept Resp & Crit Care Med, Natl Ctr Gerontol, Beijing 100730, Peoples R China

[2] Juntendo Univ, Div Resp Med, Fac Med, Bunkyo Ku, 2-1-1 Hongo, Tokyo 1138421, Japan

[3] Grad Sch Med, Bunkyo Ku, 2-1-1 Hongo, Tokyo 1138421, Japan

[4] Juntendo Univ, Grad Sch Med, Res Inst Dis Old Ages, Bunkyo Ku, 2-1-1 Hongo, Tokyo 1138421, Japan

[5] Kanagawa Cardiovasc & Resp Ctr, Dept Resp Med, Kanazawa Ku, 6-16-1 Tomiokahigashi, Yokohama, Kanagawa 2360051, Japan

[6] Natl Inst Genet, Ctr Informat Biol, 1111 Yata, Mishima, Shizuoka 4118540, Japan

[7] SOKENDAI, Dept Genet, 1111 Yata, Mishima, Shizuoka 4118540, Japan

[8] Juntendo Univ, Urayasu Hosp, Dept Resp Med, Chiba 2790001, Japan

[9] Juntendo Univ, Fac Med, Div Resp Med, Bunkyo Ku, 3-1-3 Hongo, Tokyo 1138421, Japan

[10] Grad Sch Med, Bunkyo Ku, 3-1-3 Hongo, Tokyo 1138421, Japan

来源：

RESPIRATORY RESEARCH | 2019年 / 20卷 / 1期

关键词：

Pirfenidone; Collagen triple helix repeat containing protein 1(CTHRC1); Four-and-a-half LIM domain protein 2(FHL-2); BMP-4; Transforming growth factor-1; Lung fibroblast; Lung fibrosis; TRIPLE-HELIX REPEAT; BLEOMYCIN HAMSTER MODEL; GROWTH-FACTOR-BETA; ONLY PROTEIN FHL2; COLLAGEN GEL CONTRACTION; GENE-EXPRESSION; TRANSCRIPTIONAL LEVEL; PULMONARY-FIBROSIS; PROLIFERATION; DIFFERENTIATION;

D O I：

10.1186/s12931-019-1093-z

中图分类号：

R56 [呼吸系及胸部疾病];

学科分类号：

摘要：

BackgroundPirfenidone, an antifibrotic agent used for the treatment of idiopathic pulmonary fibrosis (IPF), functions by inhibiting myofibroblast differentiation, which is involved in transforming growth factor (TGF)-1-induced IPF pathogenesis. However, unlike normal lung fibroblasts, the relationship between pirfenidone responses of TGF-1-induced human fibrotic lung fibroblasts and lung fibrosis has not been elucidated.MethodsThe effects of pirfenidone were evaluated in lung fibroblasts isolated from fibrotic human lung tissues after TGF-1 exposure. The ability of two new pharmacological targets of pirfenidone, collagen triple helix repeat containing protein 1(CTHRC1) and four-and-a-half LIM domain protein 2 (FHL2), to mediate contraction of collagen gels and migration toward fibronectin were assessed in vitro.ResultsCompared to control lung fibroblasts, pirfenidone significantly restored TGF-1-stimulated fibroblast-mediated collagen gel contraction, migration, and CTHRC1 release in lung fibrotic fibroblasts. Furthermore, pirfenidone attenuated TGF-1- and CTHRC1-induced fibroblast activity, upregulation of bone morphogenic protein-4(BMP-4)/Gremlin1, and downregulation of -smooth muscle actin, fibronectin, and FHL2, similar to that observed post-CTHRC1 inhibition. In contrast, FHL2 inhibition suppressed migration and fibronectin expression, but did not downregulate CTHRC1.ConclusionsOverall, pirfenidone suppressed fibrotic fibroblast-mediated fibrotic processes via inverse regulation of CTHRC1-induced lung fibroblast activity. Thus, CTHRC1 can be used for predicting pirfenidone response and developing new therapeutic targets for lung fibrosis.

引用

页数：14

共 56 条

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