Circulating matrix metalloproteinases and tissue metalloproteinase inhibitors in patients with idiopathic pulmonary fibrosis in the multicenter IPF-PRO Registry cohort

Jamie L. Todd, Richard Vinisko, Yi Liu, Megan L. Neely, Robert Overton, Kevin R. Flaherty, Imre Noth, L. Kristin Newby, Joseph A. Lasky, Mitchell A. Olman, Christian Hesslinger, Thomas B. Leonard, Scott M. Palmer, John A. Belperio, Wael Asi, Albert Baker, Scott Beegle, Rany Condos, Francis Cordova, Daniel A. CulverTracey Luckhardt, Daniel Dilling, Marilyn Glassberg, Mridu Gulati, Kalpalatha Guntupalli, Nishant Gupta, David Hotchkin, Tristan Huie, Robert Kaner, Hyun Kim, Maryl Kreider, Lisa Lancaster, David Lederer, Doug Lee, Timothy Liesching, Randolph Lipchik, Jason Lobo, Yolanda Mageto, Prema Menon, Lake Morrison, Andrew Namen, Justin Oldham, Rishi Raj, Murali Ramaswamy, Tonya Russell, Paul Sachs, Zeenat Safdar, Barry Sigal, Leann Silhan, Mary Strek, Sally Suliman, Jeremy Tabak, Rajat Walia, Timothy P. Whelan

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) play important roles in the turnover of extracellular matrix and in the pathogenesis of idiopathic pulmonary fibrosis (IPF). This study aimed to determine the utility of circulating MMPs and TIMPs in distinguishing patients with IPF from controls and to explore associations between MMPs/TIMPs and measures of disease severity in patients with IPF. Methods: The IPF cohort (n = 300) came from the IPF-PRO Registry, an observational multicenter registry of patients with IPF that was diagnosed or confirmed at the enrolling center in the past 6 months. Controls (n = 100) without known lung disease came from a population-based registry. Generalized linear models were used to compare circulating concentrations of MMPs 1, 2, 3, 7, 8, 9, 12, and 13 and TIMPs 1, 2, and 4 between patients with IPF and controls, and to investigate associations between circulating levels of these proteins and measures of IPF severity. Multivariable models were fit to identify the MMP/TIMPs that best distinguished patients with IPF from controls. Results: All the MMP/TIMPs analyzed were present at significantly higher levels in patients with IPF compared with controls except for TIMP2. Multivariable analyses selected MMP8, MMP9 and TIMP1 as top candidates for distinguishing patients with IPF from controls. Higher concentrations of MMP7, MMP12, MMP13 and TIMP4 were significantly associated with lower diffusion capacity of the lung for carbon monoxide (DLCO) % predicted and higher composite physiologic index (worse disease). MMP9 was associated with the composite physiologic index. No MMP/TIMPs were associated with forced vital capacity % predicted. Conclusions: Circulating MMPs and TIMPs were broadly elevated among patients with IPF. Select MMP/TIMPs strongly associated with measures of disease severity. Our results identify potential MMP/TIMP targets for further development as disease-related biomarkers.

Original languageEnglish (US)
Article number64
JournalBMC Pulmonary Medicine
Volume20
Issue number1
DOIs
StatePublished - Mar 14 2020

Keywords

  • Biomarkers
  • Extracellular matrix
  • Fibrosis
  • Interstitial lung diseases
  • Observational study

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

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