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. Culver; Tracey 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

doi:10.1186/s12890-020-1103-4

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 journal › Article › peer-review

47 Scopus citations

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 (DL_CO) % 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 language	English (US)
Article number	64
Journal	BMC Pulmonary Medicine
Volume	20
Issue number	1
DOIs	https://doi.org/10.1186/s12890-020-1103-4
State	Published - Mar 14 2020
Externally published	Yes

Keywords

Biomarkers
Extracellular matrix
Fibrosis
Interstitial lung diseases
Observational study

ASJC Scopus subject areas

Pulmonary and Respiratory Medicine

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10.1186/s12890-020-1103-4

Cite this

Todd, J. L., Vinisko, R., Liu, Y., Neely, M. L., Overton, R., Flaherty, K. R., Noth, I., Newby, L. K., Lasky, J. A., Olman, M. A., Hesslinger, C., Leonard, T. B., Palmer, S. M., Belperio, J. A., Asi, W., Baker, A., Beegle, S., Condos, R., Cordova, F., ... Whelan, T. P. (2020). Circulating matrix metalloproteinases and tissue metalloproteinase inhibitors in patients with idiopathic pulmonary fibrosis in the multicenter IPF-PRO Registry cohort. BMC Pulmonary Medicine, 20(1), Article 64. https://doi.org/10.1186/s12890-020-1103-4

Todd, JL, Vinisko, R, Liu, Y, Neely, ML, Overton, R, Flaherty, KR, Noth, I, Newby, LK, Lasky, JA, Olman, MA, Hesslinger, C, Leonard, TB, Palmer, SM, Belperio, JA, Asi, W, Baker, A, Beegle, S, Condos, R, Cordova, F, Culver, DA, Luckhardt, T, Dilling, D, Glassberg, M, Gulati, M, Guntupalli, K, Gupta, N, Hotchkin, D, Huie, T, Kaner, R, Kim, H, Kreider, M, Lancaster, L, Lederer, D, Lee, D, Liesching, T, Lipchik, R, Lobo, J, Mageto, Y, Menon, P, Morrison, L, Namen, A, Oldham, J, Raj, R, Ramaswamy, M, Russell, T, Sachs, P, Safdar, Z, Sigal, B, Silhan, L, Strek, M, Suliman, S, Tabak, J, Walia, R & Whelan, TP 2020, 'Circulating matrix metalloproteinases and tissue metalloproteinase inhibitors in patients with idiopathic pulmonary fibrosis in the multicenter IPF-PRO Registry cohort', BMC Pulmonary Medicine, vol. 20, no. 1, 64. https://doi.org/10.1186/s12890-020-1103-4

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

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.",

keywords = "Biomarkers, Extracellular matrix, Fibrosis, Interstitial lung diseases, Observational study",

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

note = "Publisher Copyright: {\textcopyright} 2020 The Author(s).",

year = "2020",

month = mar,

day = "14",

doi = "10.1186/s12890-020-1103-4",

language = "English (US)",

volume = "20",

journal = "BMC Pulmonary Medicine",

issn = "1471-2466",

publisher = "BioMed Central",

number = "1",

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TY - JOUR

T1 - Circulating matrix metalloproteinases and tissue metalloproteinase inhibitors in patients with idiopathic pulmonary fibrosis in the multicenter IPF-PRO Registry cohort

AU - Todd, Jamie L.

AU - Vinisko, Richard

AU - Liu, Yi

AU - Neely, Megan L.

AU - Overton, Robert

AU - Flaherty, Kevin R.

AU - Noth, Imre

AU - Newby, L. Kristin

AU - Lasky, Joseph A.

AU - Olman, Mitchell A.

AU - Hesslinger, Christian

AU - Leonard, Thomas B.

AU - Palmer, Scott M.

AU - Belperio, John A.

AU - Asi, Wael

AU - Baker, Albert

AU - Beegle, Scott

AU - Condos, Rany

AU - Cordova, Francis

AU - Culver, Daniel A.

AU - Luckhardt, Tracey

AU - Dilling, Daniel

AU - Glassberg, Marilyn

AU - Gulati, Mridu

AU - Guntupalli, Kalpalatha

AU - Gupta, Nishant

AU - Hotchkin, David

AU - Huie, Tristan

AU - Kaner, Robert

AU - Kim, Hyun

AU - Kreider, Maryl

AU - Lancaster, Lisa

AU - Lederer, David

AU - Lee, Doug

AU - Liesching, Timothy

AU - Lipchik, Randolph

AU - Lobo, Jason

AU - Mageto, Yolanda

AU - Menon, Prema

AU - Morrison, Lake

AU - Namen, Andrew

AU - Oldham, Justin

AU - Raj, Rishi

AU - Ramaswamy, Murali

AU - Russell, Tonya

AU - Sachs, Paul

AU - Safdar, Zeenat

AU - Sigal, Barry

AU - Silhan, Leann

AU - Strek, Mary

AU - Suliman, Sally

AU - Tabak, Jeremy

AU - Walia, Rajat

AU - Whelan, Timothy P.

PY - 2020/3/14

Y1 - 2020/3/14

N2 - 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.

AB - 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.

KW - Biomarkers

KW - Extracellular matrix

KW - Fibrosis

KW - Interstitial lung diseases

KW - Observational study

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U2 - 10.1186/s12890-020-1103-4

DO - 10.1186/s12890-020-1103-4

M3 - Article

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AN - SCOPUS:85081733548

SN - 1471-2466

VL - 20

JO - BMC Pulmonary Medicine

JF - BMC Pulmonary Medicine

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M1 - 64

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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