Effect of an MMP-9/MMP-12 inhibitor on smoke-induced emphysema and airway remodelling in guinea pigs.
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.
Churg
Andrew
A
Department of Pathology, University of British Columbia, Vancouver, BC, Canada V6T 2B5. achurg@interchange.ubc.ca
Wang
Rona
R
Wang
Xiaoshan
X
Onnervik
Per-Ola
PO
Thim
Kerstin
K
Wright
Joanne L
JL
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
D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D003895:Desmosine