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Open Access Highly Accessed Research article

Measurement of MMP-9 and -12 degraded elastin (ELM) provides unique information on lung tissue degradation

Helene Skjøt-Arkil13*, Rikke E Clausen1, Quoc Hai Trieu Nguyen1, Yaguo Wang2, Qinlong Zheng2, Fernando J Martinez4, Cory M Hogaboam4, Meilan Han4, Lloyd B Klickstein5, Martin R Larsen6, Arkadiusz Nawrocki6, Diana J Leeming1 and Morten A Karsdal1

Author Affiliations

1 Nordic Bioscience A/S, Herlev Hovedgade 207, DK-2730, Herlev, Denmark

2 Nordic Bioscience Beijing, Beijing, China

3 Institute of Clinical Research, Odense University Hospital, Odense, Denmark

4 Division of Pulmonary and Critical Care Medicine and Department of Pathology, University of Michigan, Ann Arbor, MI, USA

5 Novartis Institutes for Biomedical Research, Cambridge, MA, USA

6 Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark

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BMC Pulmonary Medicine 2012, 12:34  doi:10.1186/1471-2466-12-34

Published: 20 July 2012

Abstract

Background

Elastin is an essential component of selected connective tissues that provides a unique physiological elasticity. Elastin may be considered a signature protein of lungs where matrix metalloprotease (MMP) -9-and -12, may be considered the signature proteases of the macrophages, which in part are responsible for tissue damage during disease progression. Thus, we hypothesized that a MMP-9/-12 generated fragment of elastin may be a relevant biochemical maker for lung diseases.

Methods

Elastin fragments were identified by mass-spectrometry and one sequence, generated by MMP-9 and -12 (ELN-441), was selected for monoclonal antibody generation and used in the development of an ELISA. Soluble and insoluble elastin from lung was cleaved in vitro and the time-dependent release of fragments was assessed in the ELN-441 assay. The release of ELN-441 in human serum from patients with chronic obstructive pulmonary disease (COPD) (n = 10) and idiopathic pulmonary fibrosis (IPF) (n = 29) were compared to healthy matched controls (n = 11).

Results

The sequence ELN-441 was exclusively generated by MMP-9 and -12 and was time-dependently released from soluble lung elastin. ELN-441 levels were 287% higher in patients diagnosed with COPD (p < 0.001) and 124% higher in IPF patients (p < 0.0001) compared with controls. ELN-441 had better diagnostic value in COPD patients (AUC 97%, p = 0.001) than in IPF patients (AUC 90%, p = 0.0001). The odds ratios for differentiating controls from COPD or IPF were 24 [2.06–280] for COPD and 50 [2.64–934] for IPF.

Conclusions

MMP-9 and -12 time-dependently released the ELN-441 epitope from elastin. This fragment was elevated in serum from patients with the lung diseases IPF and COPD, however these data needs to be validated in larger clinical settings.

Keywords:
Elastin; Extracellular matrix remodeling; Biochemical marker; Neoepitope; COPD; IPF; MMP