title: Distinct emphysema subtypes defined by quantitative CT analysis are associated with specific pulmonary matrix metalloproteinases.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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 number NCT01701869 .
authors.affiliation: Southampton NIHR Respiratory Biomedical Research Unit, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK.|Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, Southampton General Hospital, Mailpoint 810, Tremona Road, Southampton, SO16 6YD, UK.
authors.forename: Kristoffer
authors.identifier: 0000-0001-8910-3900
authors.initials: K
authors.lastname: Ostridge
authors.affiliation: Southampton NIHR Respiratory Biomedical Research Unit, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK.|Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, Southampton General Hospital, Mailpoint 810, Tremona Road, Southampton, SO16 6YD, UK.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Williams
authors.affiliation: Southampton NIHR Respiratory Biomedical Research Unit, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK.|Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, Southampton General Hospital, Mailpoint 810, Tremona Road, Southampton, SO16 6YD, UK.
authors.forename: Viktoriya
authors.initials: V
authors.lastname: Kim
authors.affiliation: Department of Radiology, University Hospital Southampton, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Harden
authors.affiliation: Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, Southampton General Hospital, Mailpoint 810, Tremona Road, Southampton, SO16 6YD, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Bourne
authors.affiliation: Primary Care & Population Sciences, University of Southampton Faculty of Medicine, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK.
authors.forename: Ngaire A
authors.initials: NA
authors.lastname: Coombs
authors.affiliation: Southampton NIHR Respiratory Biomedical Research Unit, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK.|Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, Southampton General Hospital, Mailpoint 810, Tremona Road, Southampton, SO16 6YD, UK.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Elkington
authors.affiliation: Department of Radiology, Laboratory of Mathematics in Imaging, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Raul San Jose
authors.initials: RS
authors.lastname: Estepar
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: George
authors.initials: G
authors.lastname: Washko
authors.affiliation: Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, Southampton General Hospital, Mailpoint 810, Tremona Road, Southampton, SO16 6YD, UK.|Wessex Investigational Sciences Hub, University of Southampton Faculty of Medicine, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK.
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Staples
authors.affiliation: Southampton NIHR Respiratory Biomedical Research Unit, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK. t.wilkinson@soton.ac.uk.|Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, Southampton General Hospital, Mailpoint 810, Tremona Road, Southampton, SO16 6YD, UK. t.wilkinson@soton.ac.uk.|Wessex Investigational Sciences Hub, University of Southampton Faculty of Medicine, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK. t.wilkinson@soton.ac.uk.
authors.forename: Tom M A
authors.initials: TM
authors.lastname: Wilkinson
mesh_terms: D000368:Aged; D000402:Airway Obstruction / Q000000981:diagnostic imaging / Q000209:etiology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D001999:Bronchoscopy; D005260:Female; D006801:Humans; D008168:Lung / Q000201:enzymology*; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000000981:diagnostic imaging / Q000201:enzymology; D011656:Pulmonary Emphysema / Q000000981:diagnostic imaging* / Q000201:enzymology*; D012129:Respiratory Function Tests; D012907:Smoking / Q000009:adverse effects; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D014057:Tomography, X-Ray Computed
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D020782:Matrix Metalloproteinases
keywords: COPD; CT; Emphysema; Imaging; MMPs