Fibroblast growth factor 2 decreases bleomycin-induced pulmonary fibrosis and inhibits fibroblast collagen production and myofibroblast differentiation.
Fibroblast growth factor 2 decreases bleomycin-induced pulmonary fibrosis and inhibits fibroblast collagen production and myofibroblast differentiation.
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DOI：
10.1002/path.5106
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发表时间：
2018-09
期刊：
影响因子：
--
通讯作者：
Guzy RD
中科院分区：
文献类型：
--
作者：
Koo HY;El-Baz LM;House S;Cilvik SN;Dorry SJ;Shoukry NM;Salem ML;Hafez HS;Dulin NO;Ornitz DM;Guzy RD
成纤维细胞生长因子（FGF）信号传导与肺纤维化的发病机制有关。缺乏FGF 2的小鼠在博来霉素暴露后死亡率增加，上皮恢复受损，支持肺损伤后的保护或修复功能。为了确定FGF 2过表达是否减少博莱霉素诱导的损伤，我们开发了一种诱导型遗传系统，在II型肺细胞中表达FGF 2。从第0天或第7天开始，对具有多西环素诱导型人FGF 2过表达的双转基因（DTG）小鼠（SPC-rtTA; TRE-hFGF 2）或单转基因对照小鼠进行气管内博莱霉素给药并喂食多西环素饲料。此外，野生型小鼠在博来霉素治疗时开始接受气管内或静脉内重组FGF 2。与对照组相比，多西环素诱导的DTG小鼠在博来霉素后21天肺纤维化减少，如通过基因表达和组织学评估的。当在博来霉素后第0天或第7天诱导FGF 2过表达时，观察到这种有益效果。FGF 2过表达不改变上皮基因表达、支气管肺泡灌洗液细胞结构或总蛋白。使用原代小鼠和人肺成纤维细胞的体外研究表明，FGF 2强烈抑制基线和TGFβ1诱导的α平滑肌肌动蛋白（αSMA）、胶原蛋白和结缔组织生长因子的表达。虽然FGF 2不抑制Smad 2的磷酸化或Smad依赖性基因表达，但FGF 2抑制TGFβ1诱导的应激纤维形成和血清反应因子依赖性基因表达。FGF 2抑制应力纤维形成和αSMA需要FGF受体1（FGFR 1）和下游MEK/ERK，但不需要AKT信号传导。总之，FGF 2的过表达在体内可防止博莱霉素诱导的肺纤维化，在体外可逆转TGFβ1诱导的肺成纤维细胞中胶原和αSMA表达以及应力纤维形成，而不影响炎症或上皮基因表达。我们的研究结果表明，在肺，FGF 2是抗纤维化的部分通过减少胶原蛋白的表达和成纤维细胞分化成肌纤维细胞。
Fibroblast growth factor (FGF) signaling has been implicated in the pathogenesis of pulmonary fibrosis. Mice lacking FGF2 have increased mortality and impaired epithelial recovery after bleomycin exposure, supporting a protective or reparative function following lung injury. To determine whether FGF2 overexpression reduces bleomycin-induced injury, we developed an inducible genetic system to express FGF2 in type II pneumocytes. Double-transgenic (DTG) mice with doxycycline-inducible overexpression of human FGF2 (SPC-rtTA; TRE-hFGF2) or single-transgenic controls were administered intratracheal bleomycin and fed doxycycline chow, starting at either day 0 or 7. In addition, wild-type mice received intratracheal or intravenous recombinant FGF2, starting at the time of bleomycin treatment. Compared to controls, doxycycline-induced DTG mice had decreased pulmonary fibrosis 21 days after bleomycin, as assessed by gene expression and histology. This beneficial effect was seen when FGF2 overexpression was induced at day 0 or day 7 after bleomycin. FGF2 overexpression did not alter epithelial gene expression, bronchoalveolar lavage cellularity or total protein. In vitro studies using primary mouse and human lung fibroblasts showed that FGF2 strongly inhibited baseline and TGFβ1-induced expression of alpha smooth muscle actin (αSMA), collagen, and connective tissue growth factor. While FGF2 did not suppress phosphorylation of Smad2 or Smad-dependent gene expression, FGF2 inhibited TGFβ1-induced stress fiber formation and serum response factor-dependent gene expression. FGF2 inhibition of stress fiber formation and αSMA requires FGF receptor 1 (FGFR1) and downstream MEK/ERK, but not AKT signaling. In summary, overexpression of FGF2 protects against bleomycin-induced pulmonary fibrosis in vivo and reverses TGFβ1-induced collagen and αSMA expression and stress fiber formation in lung fibroblasts in vitro, without affecting either inflammation or epithelial gene expression. Our results suggest that in the lung, FGF2 is antifibrotic in part through decreased collagen expression and fibroblast to myofibroblast differentiation.
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影响因子：
4
作者：
Correia, Ana C. P.;Moonen, Jan-Renier A. J.;Krenning, Guido
通讯作者：
Krenning, Guido
影响因子：
8.8
作者：
Chen PY;Qin L;Barnes C;Charisse K;Yi T;Zhang X;Ali R;Medina PP;Yu J;Slack FJ;Anderson DG;Kotelianski V;Wang F;Tellides G;Simons M
通讯作者：
Simons M
影响因子：
4.8
作者：
Guzy, Robert D.;Li, Ling;Ornitz, David M.
通讯作者：
Ornitz, David M.
影响因子：
4.8
作者：
Cushing, Melinda C.;Mariner, Peter D.;Liao, Jo-Tsu;Sims, Evan A.;Anseth, Kristi S.
通讯作者：
Anseth, Kristi S.
DOI：
10.1164/rccm.201306-1141ws
发表时间：
2014-01-15
影响因子：
24.7
作者：
Blackwell, Timothy S.;Tager, Andrew M.;Eu, Jerry P.
通讯作者：
Eu, Jerry P.