Effect of an MMP-9/MMP-12 inhibitor on smoke-induced emphysema and airway remodelling in guinea pigs
- 1 August 2007
- Vol. 62 (8), 706-713
- https://doi.org/10.1136/thx.2006.068353
Abstract
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. 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. 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. 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.This publication has 48 references indexed in Scilit:
- The Nature of Small-Airway Obstruction in Chronic Obstructive Pulmonary DiseaseThe New England Journal of Medicine, 2004
- Alveolar macrophage-mediated elastolysis: roles of matrix metalloproteinases, cysteine, and serine proteasesAmerican Journal of Physiology-Lung Cellular and Molecular Physiology, 2002
- Metalloproteinase and growth factor interactions: do they play a role in pulmonary fibrosis?American Journal of Physiology-Lung Cellular and Molecular Physiology, 2002
- Release and Activity of Matrix Metalloproteinase-9 and Tissue Inhibitor of Metalloproteinase-1 by Alveolar Macrophages from Patients with Chronic Obstructive Pulmonary DiseaseAmerican Journal of Respiratory Cell and Molecular Biology, 2002
- The role of matrix metalloproteinase polymorphisms in the rate of decline in lung functionHuman Molecular Genetics, 2002
- Remodeling in Asthma and Chronic Obstructive Lung DiseaseAmerican Journal of Respiratory and Critical Care Medicine, 2001
- Human Collagenase (Matrix Metalloproteinase-1) Expression in the Lungs of Patients with EmphysemaAmerican Journal of Respiratory and Critical Care Medicine, 2001
- Inhibition of VEGF receptors causes lung cell apoptosis and emphysemaJCI Insight, 2000
- Upregulation of Gelatinases A and B, Collagenases 1 and 2, and Increased Parenchymal Cell Death in COPDSocial psychiatry. Sozialpsychiatrie. Psychiatrie sociale, 2000
- Elastase and matrix metalloproteinase inhibitors induce regression, and tenascin-C antisense prevents progression, of vascular diseaseJCI Insight, 2000