Distinct emphysema subtypes defined by quantitative CT analysis are associated with specific pulmonary matrix metalloproteinases

Kristoffer Ostridge, Nicholas Williams, Viktoriya Kim, Stephen Harden, Simon Bourne, Ngaire A Coombs, Paul T Elkington, Raul San Jose Estepar, George Washko, Karl J Staples, Tom M A Wilkinson, Kristoffer Ostridge, Nicholas Williams, Viktoriya Kim, Stephen Harden, Simon Bourne, Ngaire A Coombs, Paul T Elkington, Raul San Jose Estepar, George Washko, Karl J Staples, Tom M A Wilkinson

Abstract

Background: Emphysema is characterised by distinct pathological sub-types, but little is known about the divergent underlying aetiology. Matrix-metalloproteinases (MMPs) are proteolytic enzymes that can degrade the extracellular matrix and have been identified as potentially important in the development of emphysema. However, the relationship between MMPs and emphysema sub-type is unknown. We investigated the role of MMPs and their inhibitors in the development of emphysema sub-types by quantifying levels and determining relationships with these sub-types in mild-moderate COPD patients and ex/current smokers with preserved lung function.

Methods: Twenty-four mild-moderate COPD and 8 ex/current smokers with preserved lung function underwent high resolution CT and distinct emphysema sub-types were quantified using novel local histogram-based assessment of lung density. We analysed levels of MMPs and tissue inhibitors of MMPs (TIMPs) in bronchoalveolar lavage (BAL) and assessed their relationship with these emphysema sub-types.

Results: The most prevalent emphysema subtypes in COPD subjects were mild and moderate centrilobular (CLE) emphysema, while only small amounts of severe centrilobular emphysema, paraseptal emphysema (PSE) and panlobular emphysema (PLE) were present. MMP-3, and -10 associated with all emphysema sub-types other than mild CLE, while MMP-7 and -8 had associations with moderate and severe CLE and PSE. MMP-9 also had associations with moderate CLE and paraseptal emphysema. Mild CLE occurred in substantial quantities irrespective of whether airflow obstruction was present and did not show any associations with MMPs.

Conclusion: Multiple MMPs are directly associated with emphysema sub-types identified by CT imaging, apart from mild CLE. This suggests that MMPs play a significant role in the tissue destruction seen in the more severe sub-types of emphysema, whereas early emphysematous change may be driven by a different mechanism.

Trial registration: Trial registration number NCT01701869 .

Keywords: COPD; CT; Emphysema; Imaging; MMPs.

Figures

Fig. 1
Fig. 1
Local histogram emphysema (LHE) classification results for a coronal, sagittal and axial slice corresponding to (a) COPD subject and (b) subject with preserved lung function
Fig. 2
Fig. 2
BAL expression of TIMPs in subjects with COPD and preserved lung function. a TIMP-1 (b) TIMP-2 (c) TIMP-3 (d) TIMP-4. Data represents median upper and lower quartiles. Each dot represents BAL concentration of individual MMP in a specific patient, n = 24 for COPD and 8 for preserved lung function. * p < 0.05 using Mann-Whitney U test

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