title: N-alpha-PGP and PGP, potential biomarkers and therapeutic targets for COPD.
abstract: BACKGROUND
  Chronic obstructive pulmonary disease (COPD) is a common respiratory disorder for which new diagnostic and therapeutic approaches are required. Hallmarks of COPD are matrix destruction and neutrophilic airway inflammation in the lung. We have previously described two tri-peptides, N-alpha-PGP and PGP, which are collagen fragments and neutrophil chemoattractants. In this study, we investigate if N-alpha-PGP and PGP are biomarkers and potential therapeutic targets for COPD.
  
  
  METHODS
  Induced sputum samples from COPD patients, healthy controls and asthmatics were examined for levels of N-alpha-PGP and PGP using mass spectrometry and for the ability to generate PGP de novo from collagen. Proteases important in PGP generation in the lung were identified by the use of specific inhibitors in the PGP generation assay and by instillation of proteases into mouse lungs. Serum levels of PGP were compared between COPD patients and controls.
  
  
  RESULTS
  N-alpha-PGP was detected in most COPD sputum samples but in no asthmatics or controls. PGP was detected in a few controls and in all COPD sputum samples, where it correlated with levels of myeloperoxidase. COPD sputum samples had the ability to generate N-alpha-PGP and PGP de novo from collagen. PGP generation by COPD sputum was blocked by inhibitors of matrix metalloproteases (MMP's) 1 and 9 and prolyl endopeptidase. MMP's 1 and 9 and prolyl endopeptidase acted synergistically to generate PGP in vivo when instilled into mouse lungs. Serum levels of PGP were also significantly higher in COPD patients than in controls
  
  
  CONCLUSIONS
  N-alpha-PGP and PGP may represent novel diagnostic tests and biomarkers for COPD. Inhibition of this pathway may provide novel therapies for COPD directed at the chronic, neutrophilic, airway inflammation which underlies disease progression.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of Alabama at Birmingham, THT 422, 1900 University Blvd, Birmingham, Alabama 35294-0006, USA. poreilly@uab.edu
authors.forename: Philip
authors.initials: P
authors.lastname: O'Reilly
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Jackson
authors.forename: Brett
authors.initials: B
authors.lastname: Noerager
authors.forename: Suzanne
authors.initials: S
authors.lastname: Parker
authors.forename: Mark
authors.initials: M
authors.lastname: Dransfield
authors.forename: Amit
authors.initials: A
authors.lastname: Gaggar
authors.forename: J Edwin
authors.initials: JE
authors.lastname: Blalock
mesh_terms: D000818:Animals; D001249:Asthma / Q000378:metabolism / Q000503:physiopathology; D015415:Biomarkers / Q000032:analysis; D003094:Collagen / Q000378:metabolism; D005541:Forced Expiratory Volume; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000008:administration & dosage / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000008:administration & dosage / Q000378:metabolism; D051379:Mice; D009842:Oligopeptides / Q000032:analysis; D009195:Peroxidase / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism / Q000503:physiopathology*; D012016:Reference Values; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods; D013183:Sputum / Q000502:physiology; D014797:Vital Capacity
chemical_list: D015415:Biomarkers; D009842:Oligopeptides; D011480:Protease Inhibitors; D003094:Collagen; D009195:Peroxidase; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1