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 a (TNFa) were completely abolished by AZ11557272. At 6 months there was an increase in lung volumes and airspace size. AZ11557272 returned the pressurevolume 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 TNFa 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.

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

“…These findings strengthen the idea that MMP-12 is an important mediator of the anatomical changes behind COPD in humans, identifying MMP-12 as a potential therapeutic target (Churg et al, 2007). 8.1.3.4.2.…”

A therapeutic role for matrix metalloproteinase inhibitors in lung diseases?

“…Increased MMP12 activity leads to degradation of elastin, and the resultant monocyte chemotactic fragments further contribute to recruitment of eosinophils and macrophages [98] and to amplification of the inflammatory cascade [42]. Guinea pigs exposed daily to cigarette smoke for up to 6 months were protected from emphysema by the dual MMP9/MMP12 inhibitor, AZ11557272 [51]. This was reflected in a reduction of inflammatory cell numbers and desmosine levels in bronchoalveolar lavage (BAL) fluid and TNF levels in serum relative to non-treated mice.…”

Bronchopulmonary dysplasia and emphysema: in search of common therapeutic targets

“…Last, protease inhibition revealed preventing effects in animal models of emphysema [75,76]. These different trials are summarized in Table 2.…”