title: A Randomized, Placebo-controlled Trial of Roflumilast. Effect on Proline-Glycine-Proline and Neutrophilic Inflammation in Chronic Obstructive Pulmonary Disease.
abstract: BACKGROUND
  Roflumilast is a therapeutic agent in the treatment of chronic obstructive pulmonary disease (COPD). It has antiinflammatory effects; however, it is not known whether it can affect a biologic pathway implicated in COPD pathogenesis and progression. The self-propagating acetyl-proline-glycine-proline (AcPGP) pathway is a novel means of neutrophilic inflammation that is pathologic in the development of COPD. AcPGP is produced by extracellular matrix collagen breakdown with prolyl endopeptidase and leukotriene A4 hydrolase serving as the enzymes responsible for its production and degradation, respectively.
  
  
  OBJECTIVE
  We hypothesized that roflumilast would decrease AcPGP, halting the feed-forward cycle of inflammation.
  
  
  METHODS
  We conducted a single-center, placebo-controlled, randomized study investigating 12 weeks of roflumilast treatment added to current therapy in moderate-to-severe COPD with chronic bronchitis. Subjects underwent sputum and blood analyses, pulmonary function testing, exercise tolerance, and quality-of-life assessment at 0, 4, and 12 weeks.
  
  
  RESULTS
  Twenty-seven patients were enrolled in the intention-to-treat analysis. Roflumilast treatment decreased sputum AcPGP by more than 50% (P < 0.01) and prolyl endopeptidase by 46% (P = 0.02), without significant improvement in leukotriene A4 hydrolase activity compared with placebo. Roflumilast also reduces other inflammatory markers. There were no significant changes in lung function, quality of life, or exercise tolerance between roflumilast- and placebo-treated groups.
  
  
  CONCLUSIONS
  Roflumilast reduces pulmonary inflammation through decreasing prolyl endopeptidase activity and AcPGP. As expected for lower AcPGP levels, markers of neutrophilic inflammation are blunted. Inhibiting this self-propagating pathway lessens the overall inflammatory burden, which may alter the natural history of COPD, including the risk of exacerbation. Clinical trial registered with www.clinicaltrials.gov (NCT 01572948).
authors.affiliation: 1 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine.|2 UAB Lung Health Center.|3 UAB Program in Protease and Matrix Biology, and.|4 Department of Medicine, Birmingham VA Medical Center, Birmingham, Alabama.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Wells
authors.affiliation: 1 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine.|2 UAB Lung Health Center.|3 UAB Program in Protease and Matrix Biology, and.
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Jackson
authors.affiliation: 1 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine.|2 UAB Lung Health Center.|3 UAB Program in Protease and Matrix Biology, and.
authors.forename: Liliana
authors.initials: L
authors.lastname: Viera
authors.affiliation: 1 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine.|2 UAB Lung Health Center.
authors.forename: Surya P
authors.initials: SP
authors.lastname: Bhatt
authors.affiliation: 5 University of Alabama at Birmingham School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and.
authors.forename: Joshua
authors.initials: J
authors.lastname: Gautney
authors.affiliation: 5 University of Alabama at Birmingham School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and.
authors.forename: Guy
authors.initials: G
authors.lastname: Handley
authors.affiliation: 1 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine.|3 UAB Program in Protease and Matrix Biology, and.
authors.forename: R Wilson
authors.initials: RW
authors.lastname: King
authors.affiliation: 1 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine.|3 UAB Program in Protease and Matrix Biology, and.
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.affiliation: 1 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine.|3 UAB Program in Protease and Matrix Biology, and.|4 Department of Medicine, Birmingham VA Medical Center, Birmingham, Alabama.
authors.forename: Amit
authors.initials: A
authors.lastname: Gaggar
authors.affiliation: 1 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine.|2 UAB Lung Health Center.
authors.forename: William C
authors.initials: WC
authors.lastname: Bailey
authors.affiliation: 1 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine.|2 UAB Lung Health Center.|4 Department of Medicine, Birmingham VA Medical Center, Birmingham, Alabama.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Dransfield
authors.affiliation: 1 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine.|2 UAB Lung Health Center.|3 UAB Program in Protease and Matrix Biology, and.
authors.forename: J Edwin
authors.initials: JE
authors.lastname: Blalock
mesh_terms: D000368:Aged; D000631:Aminopyridines / Q000627:therapeutic use*; D001549:Benzamides / Q000627:therapeutic use*; D029481:Bronchitis, Chronic / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D003521:Cyclopropanes / Q000627:therapeutic use; D004311:Double-Blind Method; D004851:Epoxide Hydrolases / Q000276:immunology / Q000378:metabolism; D017079:Exercise Tolerance; D005260:Female; D005541:Forced Expiratory Volume; D005998:Glycine / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000276:immunology*; D058988:Phosphodiesterase 4 Inhibitors / Q000627:therapeutic use*; D011392:Proline / Q000378:metabolism; D000085822:Prolyl Oligopeptidases; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology; D011788:Quality of Life; D012697:Serine Endopeptidases / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D013147:Spirometry; D013183:Sputum / Q000201:enzymology; D016896:Treatment Outcome; D014797:Vital Capacity
chemical_list: D000631:Aminopyridines; D001549:Benzamides; D003521:Cyclopropanes; D058988:Phosphodiesterase 4 Inhibitors; C424423:Roflumilast; D011392:Proline; D004851:Epoxide Hydrolases; D012697:Serine Endopeptidases; C000705287:PREPL protein, human; D000085822:Prolyl Oligopeptidases; D005998:Glycine; C043134:leukotriene A4 hydrolase
keywords: COPD; neutrophil; proline-glycine-proline; prolyl endopeptidase; roflumilast