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An MMP-9/-12 Inhibitor Prevents Smoke-induced Emphysema and Small Airway Remodeling in Guinea Pigs
  1. Andrew Churg (achurg{at}
  1. University of British Columbia, Canada
    1. Rona Wang (rona_shan{at}
    1. University of British Columbia, Canada
      1. Xiaoshan Wang (rona_shan{at}
      1. University of British Columbia, Canada
        1. Per-Ola Onnervik (per-ola.onnervik{at}
        1. AstraZeneca R&D, Lund, Sweden
          1. Kerstin Thim (kerstin.thim{at}
          1. AstraZeneca R&D, Lund, Sweden
            1. Joanne L Wright (jlwright{at}
            1. University of British Columbia, Canada


              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 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 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 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 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.

              • Airway remodeling
              • COPD
              • Emphysema
              • MMP-12
              • MMP-9

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