An MMP-9/-12 Inhibitor Prevents Smoke-induced Emphysema and Small Airway Remodeling in Guinea Pigs

Andrew Churg ^1*, Rona Wang ¹, Xiaoshan Wang ¹, Per-Ola Onnervik ², Kerstin Thim ² and Joanne L Wright ¹

¹ University of British Columbia, Canada
² AstraZeneca R&D, Lund, Sweden

^* To whom correspondence should be addressed. E-mail: achurg{at}interchange.ubc.ca.

Accepted 24 January 2007

Abstract

Background: Matrix metalloproteases (MMPs) are believed to be important in the pathogenesis of cigarette smoke-induced emphysema, but this hypothesis has only been proven in the mouse and its applicability to other species, particularly humans, is uncertain. The role of MMPs in smoke-induced small airway remodeling is unknown. Methods: We examined the effects of a dual MMP-9/MMP-12 inhibitor, AZ11557272, on the development of anatomic and functional changes of COPD in guinea pigs exposed daily to cigarette smoke for up to 6 months. Results: At all times, smoke-induced increases in lavage inflammatory cells, lavage desmosine (a marker of elastin breakdown) and serum TNF 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 TLC, RV, and VC 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 TNF 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 morphologic emphysema, small airway remodeling, and the functional consequences of these lesions in a non-murine species. These findings strengthen the idea that MMPs are important mediators of the anatomic changes behind COPD in humans, and suggest that MMP-9 and MMP-12 may be potential intervention targets.

Keywords: Airway remodeling, COPD, Emphysema, MMP-12, MMP-9

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