title: Matrix metalloproteinase-9 predicts pulmonary status declines in α1-antitrypsin deficiency.
abstract: BACKGROUND
  Matrix metalloproteinase-9 (MMP-9) may be important in the progression of emphysema, but there have been few longitudinal clinical studies of MMP-9 including pulmonary status and COPD exacerbation outcomes.
  
  
  METHODS
  We utilized data from the placebo arm (n=126) of a clinical trial of patients with alpha1-antitrypsin deficiency (AATD) and emphysema to examine the links between plasma MMP-9 levels, pulmonary status, and COPD exacerbations over a one year observation period. Pulmonary function, computed tomography lung density, incremental shuttle walk test (ISWT), and COPD exacerbations were assessed at regular intervals over 12 months. Prospective analyses used generalized estimating equations to incorporate repeated longitudinal measurements of MMP-9 and all endpoints, controlling for age, gender, race-ethnicity, leukocyte count, and tobacco history. A secondary analysis also incorporated highly-sensitive C-reactive protein levels in predictive models.
  
  
  RESULTS
  At baseline, higher plasma MMP-9 levels were cross-sectionally associated with lower FEV1 (p=0.03), FVC (p<0.001), carbon monoxide transfer factor (p=0.03), resting oxygen saturation (p=0.02), and ISWT distance walked (p=0.02) but were not associated with radiographic lung density or total lung capacity (TLC). In longitudinal analyses, MMP-9 predicted a further decline in transfer factor (p=0.04) and oxygen saturation (p<0.001). MMP-9 also predicted worsening lung density (p=0.003), increasing TLC (p=0.02), and more frequent COPD exacerbations over follow-up (p=0.003). Controlling additionally for hs-CRP levels did not substantively change the longitudinal associations between MMP-9 and these outcomes.
  
  
  CONCLUSIONS
  Increased plasma MMP-9 levels generally predicted pulmonary status declines, including worsening transfer factor and lung density as well as greater COPD exacerbations in AATD-associated emphysema.
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA. omachi@ucsf.edu
authors.forename: Theodore A
authors.initials: TA
authors.lastname: Omachi
authors.forename: Mark D
authors.initials: MD
authors.lastname: Eisner
authors.forename: Alexis
authors.initials: A
authors.lastname: Rames
authors.forename: Lada
authors.initials: L
authors.lastname: Markovtsova
authors.forename: Paul D
authors.initials: PD
authors.lastname: Blanc
mesh_terms: D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism; D003430:Cross-Sectional Studies; D018450:Disease Progression; D017079:Exercise Tolerance; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D016014:Linear Models; D008168:Lung / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood*; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D011237:Predictive Value of Tests; D011379:Prognosis; D011446:Prospective Studies; D029424:Pulmonary Disease, Chronic Obstructive / Q000175:diagnosis / Q000201:enzymology / Q000209:etiology* / Q000503:physiopathology; D011656:Pulmonary Emphysema / Q000175:diagnosis / Q000201:enzymology / Q000209:etiology* / Q000503:physiopathology; D016032:Randomized Controlled Trials as Topic; D012720:Severity of Illness Index; D013997:Time Factors; D014109:Total Lung Capacity; D015854:Up-Regulation; D014797:Vital Capacity; D019896:alpha 1-Antitrypsin Deficiency / Q000150:complications* / Q000201:enzymology / Q000503:physiopathology
chemical_list: D015415:Biomarkers; D002097:C-Reactive Protein; D020780:Matrix Metalloproteinase 9