Article Text

other Versions

PDF

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

              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 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

              Statistics from Altmetric.com

              Request permissions

              If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

              Linked Articles

              • Airwaves
                Wisia Wedzicha