title: MMP1 and MMP7 as potential peripheral blood biomarkers in idiopathic pulmonary fibrosis.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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%).
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Ivan O
authors.initials: IO
authors.lastname: Rosas
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Richards
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Konishi
authors.forename: Yingze
authors.initials: Y
authors.lastname: Zhang
authors.forename: Kevin
authors.initials: K
authors.lastname: Gibson
authors.forename: Anna E
authors.initials: AE
authors.lastname: Lokshin
authors.forename: Kathleen O
authors.initials: KO
authors.lastname: Lindell
authors.forename: Jose
authors.initials: J
authors.lastname: Cisneros
authors.forename: Sandra D
authors.initials: SD
authors.lastname: Macdonald
authors.forename: Annie
authors.initials: A
authors.lastname: Pardo
authors.forename: Frank
authors.initials: F
authors.lastname: Sciurba
authors.forename: James
authors.initials: J
authors.lastname: Dauber
authors.forename: Moises
authors.initials: M
authors.lastname: Selman
authors.forename: Bernadette R
authors.initials: BR
authors.lastname: Gochuico
authors.forename: Naftali
authors.initials: N
authors.lastname: Kaminski
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D004796:Clinical Enzyme Tests; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008168:Lung / Q000378:metabolism; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000097:blood*; D020783:Matrix Metalloproteinase 7 / Q000097:blood*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011658:Pulmonary Fibrosis / Q000097:blood / Q000175:diagnosis*
chemical_list: D015415:Biomarkers; D020783:Matrix Metalloproteinase 7; D020781:Matrix Metalloproteinase 1