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

Jamie L Todd,L Kristin Newby,Imre Noth,Mitchell A Olman,Scott M Palmer,Robert Overton,Kevin R Flaherty,John A Belperio,Thomas B Leonard,Richard Vinisko,Joseph A Lasky,Yi Liu,Christian Hesslinger,Megan L Neely

doi:10.1186/s12890-020-1103-4

Abstract

BackgroundMatrix 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.MethodsThe 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.ResultsAll 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.ConclusionsCirculating 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.

Highlights

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)
Given that prior reports suggest that circulating MMP or TIMP expression can be altered in smoking-related respiratory diseases such as chronic obstructive pulmonary disease and emphysema [21, 22], and a substantial proportion of the patients with IPF and controls in our study were former smokers, we investigated whether there were differences in MMP or TIMP expression by current/past versus never smoking status
The association between MMPs/TIMPs and composite physiologic index (CPI) appeared to be driven mostly by DLCO % predicted, as no MMP/TIMP significantly associated with FVC % predicted

Summary

Introduction

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. Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease associated with high mortality [1]. Two anti-fibrotic agents, nintedanib and pirfenidone, have been approved for the treatment of IPF and demonstrated to slow the progression of the disease [2, 3]. The pathobiology of IPF involves excess production of extracellular matrix (ECM) and dysregulated matrix remodeling [4]. Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases important in ECM degradation. Expression of MMPs and their physiological inhibitors, tissue inhibitors of MMPs (TIMPs), is tightly regulated in the lung, with notable upregulation during lung development, tissue injury, and host defense [5]

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