Rosas Ivan O, Richards Thomas J, Konishi Kazuhisa, Zhang Yingze, Gibson Kevin, Lokshin Anna E, Lindell Kathleen O, Cisneros Jose, Macdonald Sandra D, Pardo Annie, Sciurba Frank, Dauber James, Selman Moises, Gochuico Bernadette R, Kaminski Naftali
Dorothy P. and Richard P. Simmons Center for Interstitial Lung Diseases, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School ofMedicine, Pittsburgh, Pennsylvania, United States of America.
PLoS Med. 2008 Apr 29;5(4):e93. doi: 10.1371/journal.pmed.0050093.
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic lung disease associated with substantial morbidity and mortality. The objective of this study was to determine whether there is a peripheral blood protein signature in IPF and whether components of this signature may serve as biomarkers for disease presence and progression.
We analyzed the concentrations of 49 proteins in the plasma of 74 patients with IPF and in the plasma of 53 control individuals. We identified a combinatorial signature of five proteins-MMP7, MMP1, MMP8, IGFBP1, and TNFRSF1A-that was sufficient to distinguish patients from controls with a sensitivity of 98.6% (95% confidence interval [CI] 92.7%-100%) and specificity of 98.1% (95% CI 89.9%-100%). Increases in MMP1 and MMP7 were also observed in lung tissue and bronchoalveolar lavage fluid obtained from IPF patients. MMP7 and MMP1 plasma concentrations were not increased in patients with chronic obstructive pulmonary disease or sarcoidosis and distinguished IPF compared to subacute/chronic hypersensitivity pneumonitis, a disease that may mimic IPF, with a sensitivity of 96.3% (95% CI 81.0%-100%) and specificity of 87.2% (95% CI 72.6%-95.7%). We verified our results in an independent validation cohort composed of patients with IPF, familial pulmonary fibrosis, subclinical interstitial lung disease (ILD), as well as with control individuals. MMP7 and MMP1 concentrations were significantly higher in IPF patients compared to controls in this cohort. Furthermore, MMP7 concentrations were elevated in patients with subclinical ILD and negatively correlated with percent predicted forced vital capacity (FVC%) and percent predicted carbon monoxide diffusing capacity (DLCO%).
Our experiments provide the first evidence for a peripheral blood protein signature in IPF to our knowledge. The two main components of this signature, MMP7 and MMP1, are overexpressed in the lung microenvironment and distinguish IPF from other chronic lung diseases. Additionally, increased MMP7 concentration may be indicative of asymptomatic ILD and reflect disease progression.
特发性肺纤维化（IPF）是一种慢性进行性纤维化肺病，具有较高的发病率和死亡率。本研究的目的是确定IPF患者外周血中是否存在蛋白质特征，以及该特征的组成成分是否可作为疾病存在和进展的生物标志物。
我们分析了74例IPF患者血浆和53例对照个体血浆中49种蛋白质的浓度。我们鉴定出由基质金属蛋白酶7（MMP7）、基质金属蛋白酶1（MMP1）、基质金属蛋白酶8（MMP8）、胰岛素样生长因子结合蛋白1（IGFBP1）和肿瘤坏死因子受体超家族成员1A（TNFRSF1A）这五种蛋白质组成的组合特征，该特征足以区分患者与对照，灵敏度为98.6%（95%置信区间[CI]92.7%-100%），特异性为98.1%（95%CI 89.9%-100%）。在IPF患者的肺组织和支气管肺泡灌洗液中也观察到MMP1和MMP7升高。慢性阻塞性肺疾病或结节病患者的MMP7和MMP1血浆浓度未升高，与可能模拟IPF的亚急性/慢性过敏性肺炎相比，MMP7和MMP1血浆浓度可区分IPF，灵敏度为96.3%（95%CI 81.0%-100%），特异性为87.2%（95%CI 72.6%-95.7%）。我们在一个独立的验证队列中验证了我们的数据，该队列由IPF患者、家族性肺纤维化患者、亚临床间质性肺疾病（ILD）患者以及对照个体组成。在该队列中，IPF患者的MMP7和MMP1浓度显著高于对照。此外，亚临床ILD患者的MMP7浓度升高，且与预计用力肺活量百分比（FVC%）和预计一氧化碳弥散量百分比（DLCO%）呈负相关。
据我们所知，我们的实验首次为IPF患者外周血蛋白质特征提供了证据。该特征的两个主要成分MMP7和MMP1在肺微环境中过表达，可将IPF与其他慢性肺病区分开来。此外，MMP7浓度升高可能提示无症状ILD，并反映疾病进展。
