表型-分型可能预测进行性纤维化间质性肺疾病的治疗反应。
Endotype-phenotyping may predict a treatment response in progressive fibrosing interstitial lung disease.
机构信息
Department of Rheumatology, Oslo University Hospital, Rikshospitalet, Pb 4950 Nydalen, 0424 Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Rikshospitalet, Pb 4950 Nydalen, 0424 Oslo, Norway.
Department of Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095, USA.
出版信息
EBioMedicine. 2019 Dec;50:379-386. doi: 10.1016/j.ebiom.2019.10.050. Epub 2019 Nov 12.
BACKGROUND
Some interstitial lung disease (ILD) patients develop a progressive fibrosing-ILD phenotype (PF-ILD), with similar persistent lung function decline suggesting common molecular pathways involved. Nintedanib, a tyrosine kinase inhibitor targeting the PDGF, FGF, VEGF and M-CSF pathways, has shown comparable efficacy in idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-associated ILD (SSc-ILD). We hypothesize that Nintedanib targeted molecular pathways will be augmented to a similar degree across PF-ILD regardless of aetiology.
METHODS
We collected explanted lung tissue at the time of lung transplantation from 130 PF-ILD patients (99 (76%) IPF, 14 (11%) SSc-ILD, 17 (13%) other PF-ILD), and wedge biopsies from 200 donor lungs and measured PDGF, FGF, VEGF and M-CSF concentrations by Luminex.
FINDINGS
The concentrations of PDGF-AA, PDGF-BB, FGF-2, VEGF and M-CSF were significantly increased in PF-ILD lungs compared to donor lungs (PDGF-AA 93·0 pg/ml [±97·2] vs. 37·5 pg/ml [±35·4], p < 0·001; PDGF-BB 102·5 pg/ml [±78·8] vs. 61·9 pg/ml [±47·0], p < 0·001; FGF-2 1442·4 pg/ml [±426·6] vs. 1201·7 pg/ml [±535·2], p = 0·009; VEGF 40·6 pg/ml [±20·1] vs. 24·9 pg/ml [±29·5], p < 0·001; and M-CSF 25526 pg/ml [±24,799] vs. 6120 pg/ml [±7245], p < 0·001). There were no significant differences in these growth factor/angiogenic molecules/cytokine concentrations when segregated by IPF, SSc-ILD and other PF-ILDs.
INTERPRETATION
Nintedanib specific targeted molecular pathways are augmented to a similar magnitude in all PF-ILD lung tissue as compared to controls, suggesting that Nintedanib treatment may be efficacious in PF-ILD regardless of aetiology. We speculate that clinical trials using Nintedanib for PF-ILD with or without IPF or SSc-ILD should show a similar relative reduction in FVC decline as seen in IPF and SSc-ILD (∼45-50%).
FUNDING
Health Grant P01-HL108793 (JAB), South-Eastern Norway Regional Health Authority Grant 2018072 (AMHV).
背景
部分间质性肺病（ILD）患者出现进行性纤维化-ILD 表型（PF-ILD），类似的持续肺功能下降提示存在共同的分子途径。尼达尼布是一种针对 PDGF、FGF、VEGF 和 M-CSF 途径的酪氨酸激酶抑制剂，在特发性肺纤维化（IPF）和系统性硬皮病相关间质性肺病（SSc-ILD）中显示出相当的疗效。我们假设尼达尼布针对的分子途径在 PF-ILD 中无论病因如何，其增强程度相似。
方法
我们收集了 130 名 PF-ILD 患者（99 名（76%）为 IPF、14 名（11%）为 SSc-ILD、17 名（13%）为其他 PF-ILD）肺移植时的肺组织样本和 200 名供体肺的楔形活检，通过 Luminex 测量 PDGF、FGF、VEGF 和 M-CSF 的浓度。
结果
与供体肺相比，PF-ILD 肺组织中 PDGF-AA、PDGF-BB、FGF-2、VEGF 和 M-CSF 的浓度明显升高（PDGF-AA 93.0 pg/ml[±97.2]比 37.5 pg/ml[±35.4]，p<0.001；PDGF-BB 102.5 pg/ml[±78.8]比 61.9 pg/ml[±47.0]，p<0.001；FGF-2 1442.4 pg/ml[±426.6]比 1201.7 pg/ml[±535.2]，p=0.009；VEGF 40.6 pg/ml[±20.1]比 24.9 pg/ml[±29.5]，p<0.001；和 M-CSF 25526 pg/ml[±24799]比 6120 pg/ml[±7245]，p<0.001）。当根据 IPF、SSc-ILD 和其他 PF-ILD 进行分组时，这些生长因子/血管生成分子/细胞因子的浓度没有显著差异。
结论
与对照相比，尼达尼布在所有 PF-ILD 肺组织中的特定靶向分子途径均有相似程度的增强，提示尼达尼布治疗可能对 PF-ILD 有效，无论病因如何。我们推测，使用尼达尼布治疗 PF-ILD 无论是否伴有 IPF 或 SSc-ILD 的临床试验，应显示出与 IPF 和 SSc-ILD 相似的 FVC 下降相对减少（约 45-50%）。
资金
健康补助金 P01-HL108793（JAB），东南挪威地区卫生局补助金 2018072（AMHV）。
Zotero 插件