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Circulating matrix metalloproteinases and tissue metalloproteinase inhibitors in patients with idiopathic pulmonary fibrosis in the multicenter IPF-PRO Registry cohort.
BMC Pulm Med. 2020 Mar 14; 20(1):64.BP

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.

Authors+Show Affiliations

Duke Clinical Research Institute, Durham, NC, USA. jamie.todd@duke.edu. Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Duke University Medical Center, DUMC Box 103002, Durham, NC, 27710, USA. jamie.todd@duke.edu.Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA.Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA.Duke Clinical Research Institute, Durham, NC, USA. Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Duke University Medical Center, DUMC Box 103002, Durham, NC, 27710, USA.Duke Clinical Research Institute, Durham, NC, USA.Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA.University of Virginia, Charlottesville, VA, USA.Duke Clinical Research Institute, Durham, NC, USA. Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Duke University Medical Center, DUMC Box 103002, Durham, NC, 27710, USA. Duke Clinical & Translational Science Institute, Durham, NC, USA.School of Medicine, Tulane University, New Orleans, LA, USA.Department of Inflammation and Immunity and Respiratory Institute, Cleveland Clinic, Cleveland, OH, USA.Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA.Duke Clinical Research Institute, Durham, NC, USA. Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Duke University Medical Center, DUMC Box 103002, Durham, NC, 27710, USA.David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.No affiliation info available

Pub Type(s)

Journal Article
Multicenter Study
Observational Study

Language

eng

PubMed ID

32171287

Citation

Todd, Jamie L., et al. "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, 2020, p. 64.
Todd JL, Vinisko R, Liu Y, et al. Circulating matrix metalloproteinases and tissue metalloproteinase inhibitors in patients with idiopathic pulmonary fibrosis in the multicenter IPF-PRO Registry cohort. BMC Pulm Med. 2020;20(1):64.
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. (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), 64. https://doi.org/10.1186/s12890-020-1103-4
Todd JL, et al. Circulating Matrix Metalloproteinases and Tissue Metalloproteinase Inhibitors in Patients With Idiopathic Pulmonary Fibrosis in the Multicenter IPF-PRO Registry Cohort. BMC Pulm Med. 2020 Mar 14;20(1):64. PubMed PMID: 32171287.
* Article titles in AMA citation format should be in sentence-case
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 - ,, Y1 - 2020/03/14/ PY - 2019/07/29/received PY - 2020/02/28/accepted PY - 2020/3/16/entrez PY - 2020/3/17/pubmed PY - 2021/1/21/medline KW - Biomarkers KW - Extracellular matrix KW - Fibrosis KW - Interstitial lung diseases KW - Observational study SP - 64 EP - 64 JF - BMC pulmonary medicine JO - BMC Pulm Med VL - 20 IS - 1 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. SN - 1471-2466 UR - https://www.unboundmedicine.com/medline/citation/32171287/Circulating_matrix_metalloproteinases_and_tissue_metalloproteinase_inhibitors_in_patients_with_idiopathic_pulmonary_fibrosis_in_the_multicenter_IPF_PRO_Registry_cohort_ L2 - https://bmcpulmmed.biomedcentral.com/articles/10.1186/s12890-020-1103-4 DB - PRIME DP - Unbound Medicine ER -