Effect of an MMP-9/MMP-12 inhibitor on smoke-induced emphysema and airway remodelling in guinea pigs
Autor: | Per-Ola Onnervik, Rona Wang, Kerstin Thim, Andrew Churg, Joanne L. Wright, Xiaoshan Wang |
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Rok vydání: | 2007 |
Předmět: |
Pulmonary and Respiratory Medicine
Pathology medicine.medical_specialty Chronic Obstructive Pulmonary Disease Guinea Pigs Bronchi Matrix Metalloproteinase Inhibitors Desmosine Pathogenesis chemistry.chemical_compound Pulmonary Disease Chronic Obstructive medicine.artery Medicine Animals Lung volumes Enzyme Inhibitors Small Airway Remodeling COPD business.industry Tumor Necrosis Factor-alpha Respiratory disease Smoking Bronchial Diseases medicine.disease medicine.anatomical_structure chemistry Pulmonary Emphysema Pulmonary artery Female business Bronchoalveolar Lavage Fluid Respiratory tract |
Zdroj: | Thorax. 62(8) |
ISSN: | 0040-6376 |
Popis: | 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 α (TNFα) 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 TNFα 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. |
Databáze: | OpenAIRE |
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