Increased Matrix Metalloproteinase (MMPs) Levels Do Not Predict Disease Severity or Progression in Emphysema

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. © 2013 D'Armiento et al

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

RationaleThough 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.MethodsEnzyme-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 resultsCompared 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.ConclusionsMMPs 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

Association between quartile of BALF protein expression and clinical parameters.

<p>The mean values of age, pack years, FEV1% predicted, FEV1/FVC % predicted, TLC % predicted, CT score and St. George questionnaire total score were calculated for each quartile of MMP-1, -9, -12 and TIMP-1 BALF protein expression. Bold indicates p<0.05 compared to quartile 1. Parentheses () indicate standard deviation.</p

Correlation between plasma MMP/TIMP levels and % change in FEV1.

<p>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.</p

Correlation between BALF MMP/TIMP levels and % change in FEV1.

<p>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.</p

Patient Demographics.

<p>Data are presented as mean ± standard deviation.</p

Quartiles of MMP protein expression.

<p>Minimum to 25% represented quartile 1 (Q1), 26% to Median represented quartile 2 (Q2), Median to 75% represented quartile 3 (Q3) and 75% to Maximum represented quartile 4 (Q4).</p

Correlation between MMPs and DL_CO or FEV1/FVC % predicted.

<p>Linear regression analyses correlated baseline BALF MMP-1, -9, -12 and TIMP-1 lavage levels with change in DL_CO or the FEV1/FVC % predicted ratio at 9-month follow up. R² = coefficient of correlation.</p

Correlation between baseline and follow up BALF and plasma MMP/TIMP levels.

<p>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.</p