Increased FGF1-FGFRc expression in idiopathic pulmonary fibrosis.
Increased FGF1-FGFRc expression in idiopathic pulmonary fibrosis.
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DOI：
10.1186/s12931-015-0242-2
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发表时间：
2015-07-03
影响因子：
5.8
通讯作者：
Bellusci S
中科院分区：
文献类型：
--
作者：
MacKenzie B;Korfei M;Henneke I;Sibinska Z;Tian X;Hezel S;Dilai S;Wasnick R;Schneider B;Wilhelm J;El Agha E;Klepetko W;Seeger W;Schermuly R;Günther A;Bellusci S
最近的临床研究表明，酪氨酸激酶抑制剂可以减缓特发性肺纤维化（IPF）患者肺功能下降的速度并减少急性加重的次数。然而，在鼠类博莱霉素纤维化模型中，并非所有酪氨酸激酶信号传导都是有害的。外源配体成纤维细胞生长因子 (FGF) 7 和 10 通过酪氨酸激酶 FGF 受体 2b 信号传导改善小鼠肺修复并提高损伤后的存活率。因此，我们分析了人肺成纤维细胞中 FGF/FGFR 表达的水平和位置以及最高表达的 FGFR2b 配体 FGF1 的外源效应。使用蛋白质印迹和 qPCR 评估供体和 IPF 全肺匀浆中的 FGF 配体和受体表达。对人肺组织进行 FGF1 和 FGFR1/2/3/4 的免疫组织化学分析。最后，研究了 FGF1（一种有效的多 FGFR 配体）对 IPF 和非 IPF 供体成纤维细胞原代培养物的影响。对细胞培养物进行促纤维化标记物、增殖的蛋白质印迹、细胞凋亡的 FACS、transwell 测定和 MetaMorph 分析。全肺匀浆分析显示 FGFR b-亚型表达减少，FGFR c-亚型表达增加。在 FGFR2b 配体中，FGF1 在 IPF 患者中增加最为显着； FGF 信号、p-ERK1/2 和 p-AKT 的下游靶标也增加。免疫组织化学显示 FGF1 在基底细胞片、肌成纤维细胞灶和表面活性蛋白 C 阳性肺泡上皮 II 型细胞内共定位，并与 FGFR1、FGFR2、FGFR3、FGFR4 和表达迁移标记肌成束蛋白的肌成纤维细胞共定位。无论是单独使用还是在肝素存在下，FGF1 都会导致原代肺成纤维细胞中 MAPK 信号传导增强。虽然平滑肌肌动蛋白没有变化，但肝素 + FGF1 减少了 IPF 成纤维细胞中胶原蛋白的产生。此外，FGF1 + 肝素可增加细胞凋亡和细胞迁移。 FGFR 抑制剂 (PD173074) 减弱了这些影响。 FGF1/FGFR 在 IPF 致病区域的强表达表明，异常的 FGF1-FGFR 信号在 IPF 患者中增加，并可能通过支持成纤维细胞迁移和增加的 MAPK 信号而促进肺纤维化的发病机制。本文的在线版本 (doi:10.1186/s12931-015-0242-2) 包含补充材料，可供授权用户使用。
Recent clinical studies show that tyrosine kinase inhibitors slow the rate of lung function decline and decrease the number of acute exacerbations in patients with Idiopathic Pulmonary Fibrosis (IPF). However, in the murine bleomycin model of fibrosis, not all tyrosine kinase signaling is detrimental. Exogenous ligands Fibroblast Growth Factor (FGF) 7 and 10 improve murine lung repair and increase survival after injury via tyrosine kinase FGF receptor 2b-signaling. Therefore, the level and location of FGF/FGFR expression as well as the exogenous effect of the most highly expressed FGFR2b ligand, FGF1, was analyzed on human lung fibroblasts. FGF ligand and receptor expression was evaluated in donor and IPF whole lung homogenates using western blotting and qPCR. Immunohistochemistry for FGF1 and FGFR1/2/3/4 were performed on human lung tissue. Lastly, the effects of FGF1, a potent, multi-FGFR ligand, were studied on primary cultures of IPF and non-IPF donor fibroblasts. Western blots for pro-fibrotic markers, proliferation, FACS for apoptosis, transwell assays and MetaMorph analyses on cell cultures were performed. Whole lung homogenate analyses revealed decreased FGFR b-isoform expression, and an increase in FGFR c-isoform expression. Of the FGFR2b-ligands, FGF1 was the most significantly increased in IPF patients; downstream targets of FGF-signaling, p-ERK1/2 and p-AKT were also increased. Immunohistochemistry revealed FGF1 co-localization within basal cell sheets, myofibroblast foci, and Surfactant protein-C positive alveolar epithelial type-II cells as well as co-localization with FGFR1, FGFR2, FGFR3, FGFR4 and myofibroblasts expressing the migratory marker Fascin. Both alone and in the presence of heparin, FGF1 led to increased MAPK-signaling in primary lung fibroblasts. While smooth muscle actin was unchanged, heparin + FGF1 decreased collagen production in IPF fibroblasts. In addition, FGF1 + heparin increased apoptosis and cell migration. The FGFR inhibitor (PD173074) attenuated these effects. Strong expression of FGF1/FGFRs in pathogenic regions of IPF suggest that aberrant FGF1-FGFR signaling is increased in IPF patients and may contribute to the pathogenesis of lung fibrosis by supporting fibroblast migration and increased MAPK-signaling. The online version of this article (doi:10.1186/s12931-015-0242-2) contains supplementary material, which is available to authorized users.
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DOI：
10.1152/ajplung.00070.2010
发表时间：
2010-08-01
影响因子：
4.9
作者：
Ramos, Carlos;Becerril, Carina;Selman, Moises
通讯作者：
Selman, Moises
影响因子：
5.8
作者：
Chilosi, Marco;Zamo, Alberto;Poletti, Venerino
通讯作者：
Poletti, Venerino
影响因子：
5
作者：
Chilosi, M;Poletti, V;Doglioni, C
通讯作者：
Doglioni, C
影响因子：
9.6
作者：
Hanumegowda, Chandru;Farkas, Laszlo;Kolb, Martin
通讯作者：
Kolb, Martin
影响因子：
8
作者：
Liu, JL;Huang, C;Zhan, X
通讯作者：
Zhan, X