title: Effect of an MMP-9/MMP-12 inhibitor on smoke-induced emphysema and airway remodelling in guinea pigs.
abstract: BACKGROUND
  Matrix metalloproteases (MMPs) are believed to be important in the pathogenesis of cigarette smoke-induced emphysema, but this hypothesis has only been proved in the mouse and its applicability to other species, particularly humans, is uncertain. The role of MMPs in smoke-induced small airway remodelling is unknown.
  
  
  METHODS
  The effects of a dual MMP-9/MMP-12 inhibitor, AZ11557272, on the development of anatomical and functional changes of chronic obstructive pulmonary disease (COPD) in guinea pigs exposed daily to cigarette smoke for up to 6 months were examined.
  
  
  RESULTS
  At all times, smoke-induced increases in lavage inflammatory cells, lavage desmosine (a marker of elastin breakdown) and serum tumour necrosis factor alpha (TNFalpha) were completely abolished by AZ11557272. At 6 months there was an increase in lung volumes and airspace size. AZ11557272 returned the pressure- volume curve to control levels, decreased smoke-induced increases in total lung capacity, residual volume and vital capacity by about 70%, and also reversed smoke-induced airspace enlargement by about 70%. There was a very strong correlation between surface to volume ratio and both lavage desmosine and serum TNFalpha levels. AZ11557272 protected against smoke-mediated increases in small airway wall thickness but did not prevent smoke-induced increases in mean pulmonary artery pressure.
  
  
  CONCLUSIONS
  An MMP-9/MMP-12 inhibitor can substantially ameliorate morphological emphysema, small airway remodelling and the functional consequences of these lesions in a non-murine species. These findings strengthen the idea that MMPs are important mediators of the anatomical changes behind COPD in humans, and suggest that MMP-9 and MMP-12 may be potential intervention targets.
authors.affiliation: Department of Pathology, University of British Columbia, Vancouver, BC, Canada V6T 2B5. achurg@interchange.ubc.ca
authors.forename: Andrew
authors.initials: A
authors.lastname: Churg
authors.forename: Rona
authors.initials: R
authors.lastname: Wang
authors.forename: Xiaoshan
authors.initials: X
authors.lastname: Wang
authors.forename: Per-Ola
authors.initials: PO
authors.lastname: Onnervik
authors.forename: Kerstin
authors.initials: K
authors.lastname: Thim
authors.forename: Joanne L
authors.initials: JL
authors.lastname: Wright
mesh_terms: D000818:Animals; D001980:Bronchi / Q000473:pathology; D001982:Bronchial Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D003895:Desmosine / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D061965:Matrix Metalloproteinase Inhibitors; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D011656:Pulmonary Emphysema / Q000209:etiology* / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D003895:Desmosine