Anti-fibrotic effects of nintedanib in lung fibroblasts derived from patients with idiopathic pulmonary fibrosis.
Anti-fibrotic effects of nintedanib in lung fibroblasts derived from patients with idiopathic pulmonary fibrosis.
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DOI：
10.1186/s12931-014-0157-3
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发表时间：
2014-12-12
影响因子：
5.8
通讯作者：
Roth M
中科院分区：
文献类型：
--
作者：
Hostettler KE;Zhong J;Papakonstantinou E;Karakiulakis G;Tamm M;Seidel P;Sun Q;Mandal J;Lardinois D;Lambers C;Roth M
特发性肺纤维化（IPF）是一种预后不良的进行性肺部疾病。与安慰剂相比，血管内皮生长因子受体（VEGFR）、血小板衍生生长因子受体（PDGFR）和成纤维细胞生长因子受体（FGFR）特异性激酶抑制剂尼达尼布显著降低了用力肺活量下降率。确定尼达尼布对原代人肺成纤维细胞的体外影响。方法：从IPF患者和非纤维化对照的肺中分离成纤维细胞。我们评估了VEGF、PDGF-BB和碱性FGF（bFGF）±尼达尼布对以下方面的影响：（i）VEGFR、PDGFR和FGFR的表达/活化，（ii）细胞增殖，（iii）基质金属蛋白酶（MMP）、（iv）金属蛋白酶组织抑制剂（TIMP）和（v）胶原蛋白的分泌。IPF成纤维细胞表达的PDGFR和FGFR水平高于对照组。PDGF-BB、bFGF和VEGF可引起促增殖作用，尼达尼布可阻止这种作用。尼达尼布增强pro-MMP-2的表达，抑制TIMP-2的表达。尼达尼布可抑制转化生长因子β诱导的胶原分泌。我们的数据表明尼达尼布在IPF成纤维细胞中具有显著的抗纤维化作用。这种作用包括药物的抗增殖能力，以及其对细胞外基质的作用，其降解似乎得到增强。
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis. The kinase inhibitor nintedanib specific for vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR) significantly reduced the rate of decline of forced vital capacity versus placebo. To determine the in vitro effect of nintedanib on primary human lung fibroblasts. Methods: Fibroblasts were isolated from lungs of IPF patients and from non-fibrotic controls. We assessed the effect of VEGF, PDGF-BB and basic FGF (bFGF) ± nintedanib on: (i) expression/activation of VEGFR, PDGFR, and FGFR, (ii) cell proliferation, secretion of (iii) matrix metalloproteinases (MMP), (iv) tissue inhibitor of metalloproteinase (TIMP), and (v) collagen. IPF fibroblasts expressed higher levels of PDGFR and FGFR than controls. PDGF-BB, bFGF, and VEGF caused a pro-proliferative effect which was prevented by nintedanib. Nintedanib enhanced the expression of pro-MMP-2, and inhibited the expression of TIMP-2. Transforming growth factor-beta-induced secretion of collagens was inhibited by nintedanib. Our data demonstrate a significant anti-fibrotic effect of nintedanib in IPF fibroblasts. This effect consists of the drug’s anti-proliferative capacity, and on its effect on the extracellular matrix, the degradation of which seems to be enhanced.
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DOI：
10.1165/ajrcmb.27.2.4674
发表时间：
2002-08-01
影响因子：
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作者：
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发表时间：
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10.1513/pats.201203-023aw
发表时间：
2012-07-01
期刊：
Proceedings of the American Thoracic Society
影响因子：
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作者：
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通讯作者：
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DOI：
10.1164/rccm.2009-040gl
发表时间：
2011-03-15
影响因子：
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作者：
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