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. 2013;8(2):e56352.
doi: 10.1371/journal.pone.0056352. Epub 2013 Feb 18.

Increased matrix metalloproteinase (MMPs) levels do not predict disease severity or progression in emphysema

Jeanine M D'Armiento  1 , Monica P Goldklang, Andrew A Hardigan, Patrick Geraghty, Michael D Roth, John E Connett, Robert A Wise, Frank C Sciurba, Steven M Scharf, Jincy Thankachen, Monirul Islam, Andrew J Ghio, Robert F Foronjy
Affiliations

Increased matrix metalloproteinase (MMPs) levels do not predict disease severity or progression in emphysema

Jeanine M D'Armiento et al. PLoS One. 2013.

Abstract

Rationale: Though matrix metalloproteinases (MMPs) are critical in the pathogenesis of COPD, their utility as a disease biomarker remains uncertain. This study aimed to determine whether bronchoalveolar lavage (BALF) or plasma MMP measurements correlated with disease severity or functional decline in emphysema.

Methods: Enzyme-linked immunosorbent assay and luminex assays measured MMP-1, -9, -12 and tissue inhibitor of matrix metalloproteinase-1 in the BALF and plasma of non-smokers, smokers with normal lung function and moderate-to-severe emphysema subjects. In the cohort of 101 emphysema subjects correlative analyses were done to determine if MMP or TIMP-1 levels were associated with key disease parameters or change in lung function over an 18-month time period.

Main results: Compared to non-smoking controls, MMP and TIMP-1 BALF levels were significantly elevated in the emphysema cohort. Though MMP-1 was elevated in both the normal smoker and emphysema groups, collagenase activity was only increased in the emphysema subjects. In contrast to BALF, plasma MMP-9 and TIMP-1 levels were actually decreased in the emphysema cohort compared to the control groups. Both in the BALF and plasma, MMP and TIMP-1 measurements in the emphysema subjects did not correlate with important disease parameters and were not predictive of subsequent functional decline.

Conclusions: MMPs are altered in the BALF and plasma of emphysema; however, the changes in MMPs correlate poorly with parameters of disease intensity or progression. Though MMPs are pivotal in the pathogenesis of COPD, these findings suggest that measuring MMPs will have limited utility as a prognostic marker in this disease.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. BALF MMP and TIMP-1 protein levels and protease activity in controls, smokers and emphysema subjects.
BALF was performed on 72 normal control subjects, 16 smokers, and 101 subjects with moderate to severe emphysema who had refrained from smoking for at least six months. (A) MMP-1, (B) MMP-9, (C) MMP-12 and (D) TIMP-1 protein levels were recorded. p<0.0001 by Kruskal-Wallis one-way analysis of variance by ranks followed by a Dunn’s multiple comparison test. p values shown, comparing both treatments connected by a line. (E) Collagenase and (F) elastase activity were measured in the BALF of 26 normal controls, 9 smokers without emphysema and 60 emphysema subjects. Differences between cohorts was assessed by ANOVA; p<0.05. (G) MMP-1/TIMP-1 BALF ratios and (H) MMP-9/TIMP-1 BALF ratios were determined in the BALF of 82 normal controls, 18 smokers without emphysema and 98 emphysema subjects. Differences between cohorts was assessed by ANOVA; p<0.05.
Figure 2
Figure 2. MMP and TIMP-1 levels in the plasma of normal smokers and emphysema subjects.
Luminex multiplex assays for MMP-1 (top panel), MMP-9 (center panel) and TIMP-1 (bottom panel) were done on age-matched plasma samples from non-smoking controls, normal smokers and subjects with moderate to severe emphysema. MMP-12 was measured but levels were below the limit of detection.
Figure 3
Figure 3. Correlation between MMPs and DLCO or FEV1/FVC % predicted.
Linear regression analyses correlated baseline BALF MMP-1, -9, -12 and TIMP-1 lavage levels with change in DLCO or the FEV1/FVC % predicted ratio at 9-month follow up. R2 = coefficient of correlation.
Figure 4
Figure 4. Correlation between baseline and follow up BALF and plasma MMP/TIMP levels.
Baseline BALF and plasma protein levels for MMP-1, -9 and TIMP-1 were correlated with follow up MMP/TIMP levels that were collected and measured 3 or 6 months following the baseline tests. The coefficient of determination (R2) was calculated for each value at each time point.
Figure 5
Figure 5. Correlation between BALF MMP/TIMP levels and % change in FEV1.
BALF protein levels for MMP-1, -9 and TIMP-1 were correlated with the % change from baseline in FEV1 at 6, 9 and 18 months of follow up. The coefficient of determination (R2) was calculated for each value at each time point.
Figure 6
Figure 6. Correlation between plasma MMP/TIMP levels and % change in FEV1.
Plasma protein levels for MMP-1, -9 and TIMP-1 were correlated with the % change from baseline in FEV1 at 6, 9 and 18 months of follow up. The coefficient of determination (R2) was calculated for each value at each time point.
Figure 7
Figure 7. There is no correlation between BALF and plasma MMPs and TIMP-1 levels. (
A) Correlation between MMP/TIMP BALF and plasma levels. BALF protein levels for MMP-1, -9 and TIMP-1 were correlated with plasma MMP-1, -9 and TIMP-1 levels that were taken at the same time. The coefficient of determination (R2) was calculated for each value at each time point. (B) Correlation between MMP and TIMP-1 BALF levels. BALF MMP-1, -9 and -12 levels were correlated with BALF TIMP-1 levels that were taken at the same time. The coefficient of determination (R2) was calculated for each value at each time point.
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