title: Late intervention with a myeloperoxidase inhibitor stops progression of experimental chronic obstructive pulmonary disease.
abstract: BACKGROUND
  Inflammation and oxidative stress are linked to the deleterious effects of cigarette smoke in producing chronic obstructive pulmonary disease (COPD). Myeloperoxidase (MPO), a neutrophil and macrophage product, is important in bacterial killing, but also drives inflammatory reactions and tissue oxidation.
  
  
  OBJECTIVE
  To determine the role of MPO in COPD.
  
  
  METHODS
  We treated guinea pigs with a 2-thioxanthine MPO inhibitor, AZ1, in a 6-month cigarette smoke exposure model, with one group receiving compound from Smoking Day 1 and another group treated after 3 months of smoke exposure.
  
  
  RESULTS
  At 6 months both treatments abolished smoke-induced increases in lavage inflammatory cells, largely ameliorated physiological changes, and prevented or stopped progression of morphologic emphysema and small airway remodeling. Cigarette smoke caused a marked increase in immunohistochemical staining for the myeloperoxidase-generated protein oxidation marker dityrosine, and this effect was considerably decreased with both treatment arms. Serum 8-isoprostane, another marker of oxidative stress, showed similar trends. Both treatments also prevented muscularization of the small intrapulmonary arteries, but only partially ameliorated smoke-induced pulmonary hypertension. Acutely, AZ1 prevented smoke-induced increases in expression of cytokine mediators and nuclear factor-κB binding.
  
  
  CONCLUSIONS
  We conclude that an MPO inhibitor is able to stop progression of emphysema and small airway remodeling and to partially protect against pulmonary hypertension, even when treatment starts relatively late in the course of long-term smoke exposure, suggesting that inhibition of MPO may be a novel and useful therapeutic treatment for COPD. Protection appears to relate to inhibition of oxidative damage and down-regulation of the smoke-induced inflammatory response.
authors: Department of Pathology and UBC James Hogg Research Centre, Institute for Heart and Lung Health, University of British Columbia, Vancouver, British Columbia, Canada. achurg@interchange.ubc.ca
authors: Andrew
authors: A
authors: Churg
authors: Caroline V
authors: CV
authors: Marshall
authors: Don D
authors: DD
authors: Sin
authors: Sarah
authors: S
authors: Bolton
authors: Steven
authors: S
authors: Zhou
authors: Katherine
authors: K
authors: Thain
authors: Elaine B
authors: EB
authors: Cadogan
authors: Justine
authors: J
authors: Maltby
authors: Matthew G
authors: MG
authors: Soars
authors: Philip R
authors: PR
authors: Mallinder
authors: Joanne L
authors: JL
authors: Wright
mesh_terms: D056151:Airway Remodeling / Q000187:drug effects; D000818:Animals; D015237:Dinoprost / Q000031:analogs & derivatives / Q000097:blood; D004195:Disease Models, Animal; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006168:Guinea Pigs; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D009195:Peroxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism*; D011687:Purines / Q000627:therapeutic use*; D012907:Smoking / Q000009:adverse effects*; D013871:Thiones / Q000627:therapeutic use*; D013892:Thioxanthenes / Q000037:antagonists & inhibitors / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000187:drug effects
chemical_list: C570409:3-((tetrahydrofuran-2-yl)methyl)-2-thioxo-7H-purin-6-one; D004791:Enzyme Inhibitors; D011687:Purines; D013871:Thiones; D013892:Thioxanthenes; C060355:2-thioxanthene; C075750:8-epi-prostaglandin F2alpha; D014443:Tyrosine; D015237:Dinoprost; C007543:dityrosine; D009195:Peroxidase